HUP0402550A2 - Esters and amides as ppar-alpha agonists - Google Patents

Abstract

The invention deals with compounds of general formula (I), which mainly have a PPARα agonistic effect. They reduce blood glucose, lipid, and cholesterol levels, reduce body weight, and thus can be used for the prevention and treatment of diseases related to elevated lipid levels, atherosclerosis, coronary artery disease, X-syndrome, reduced glucose tolerance leading to type 2 diabetes, insulin resistance, and high blood pressure. If appropriate, the mentioned compounds can be used to inhibit HMGCoA reductase. The invention deals with the processes for the production of the mentioned compounds, also with the intermediates of the processes, and also with pharmaceutical preparations containing the above-mentioned compounds. HE

Description

700050/SZE

S. B. G. & K.

Patent Attorney's Office H-1062 Budapest, Andrássy út 113. Telephone: 461-1000, Fax: 461-1099

New compounds, their use as medicines, their production processes and pharmaceutical preparations containing the chemicals

PUBLICATION COPY

The present invention relates to antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds of general formula (I), their derivatives, analogues, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and compositions containing the same.

In particular, the present invention relates to compounds of general formula (I), especially those having PPARα agonist activity, their derivatives, analogues, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and compositions containing the same, wherein in general formula (I).

R represents hydrogen, halogen, hydroxyl, straight or branched alkyl group of 1-12 carbon atoms, straight or branched alkoxy group of 1-12 carbon atoms, alkanoyl group of 1-12 carbon atoms, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl group or together with the adjacent R ² group forms a bond R represents hydrogen, halogen, straight or branched alkyl group of 1-12 carbon atoms, straight or branched alkoxy group of 1-12 carbon atoms, alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl group or R ² together with the R ¹ group forms a bond;

R ³ represents a hydrogen atom, a substituted or unsubstituted group; a straight or branched, C 1-12 alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, C 1-12 alkanoyl, aroyl, arylalkyl, arylalkanoyl, heterocyclic, ►· 2 aryl, C 1-12 alkanoyl, aroyl, arylalkyl, arylalkanoyl, heterocyclic, heteroaryl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl or arylaminocarbonyl group;

R ⁴ represents a hydrogen atom, a straight or branched C 1-12 alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic, heteroaryl or heteroarylalkyl group;

Y represents an oxygen atom, a group of the general formula NR ⁷ or N(R ⁷ )O, where R ⁷ represents a hydrogen atom or a substituted or unsubstituted group: a straight or branched, C 1-12 alkyl, aryl, arylalkyl, hydroxyalkyl, alkanoyl, aroyl, arylalkanoyl, heterocyclic, heteroaryl, heteroarylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group;

R ⁴ and R ⁷ together may form a saturated or unsaturated 5-6 membered ring structure consisting of carbon atoms and nitrogen atoms, and optionally containing one or more additional heteroatoms, namely oxygen, sulfur or nitrogen atoms;

R ⁵ represents a hydrogen atom or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aroyl or aralkanoyl group;

Ar represents a substituted or unsubstituted divalent group of the following: phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolyl, pyrazolyl, benzothiazolyl, benzoxazolyl or the like;

X is -0(=0)-, -C(=S)-, -C(=S)-O-, -C(=O)-O-, -C(=O)-S-, -0-(CH ₂ ) _d -, -NH-(CH ₂ ) d -, -OC(-O)-, -C(=O)CH ₂ -, -CR ^a =CR ^b -CH ₂ -, -CR ^a =CR ^b -CO- or a group of the general formula, wherein R ^a and R ^b independently represent a hydrogen atom or an alkyl group having 1-6 carbon atoms, d represents an integer of 1-4; or X represents a bond;

R ⁶ represents the following substituted or unsubstituted group: aryloxycarbonyl-, arylalkoxycarbonyl-, alkylcarbonyloxy-, alkoxycarbonylamino-, aryloxycarbonylamino3 ►

aryl-alkoxycarbonyl-amino-, fluorenyl-methoxycarbonyl- (Fmoc), fluorenyl-methoxycarbonyl-amino- (N-Fmoc), -OSO ₂ R ⁸ , -OCONR ⁸ R ⁹ , NR ⁸ COOR ⁹ , -NR 8 COR 9 , -NR ⁸ SO2R ⁹ , -NR ⁸ CONR ^{9 R 10} , -NR ⁸ CSNR ^{8 R 9} , -SO2R 8 , -SOR ⁸ , -SR ⁸ , -SO2NR ^{8 R 9 ,} -SO2OR ⁸ , -COOR ⁹ , -COR ⁹ or -CONR ⁸ R ⁹ a group of the general formula, where R ⁸ , R ⁹ and R ¹⁰ independently represent a hydrogen atom or a substituted or unsubstituted group, alkyl-, aryl-, arylalkyl-, alkoxycarbonyl- or aryl-alkoxycarbonyl group; when R and R are on a nitrogen atom, they may together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms; R ⁶ represents a hydrogen atom when R ¹³ is at the 3-position of the phenyl ring and is not a hydrogen atom;

R ¹³ is hydrogen, halogen, nitro, cyano, amino, halogenated alkyl, hydroxyl or the following groups, substituted or unsubstituted: straight or branched, C1-C12 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryloxy, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl-(Fmoc), fluorenylmethoxycarbonylamino, (N-Fmoc), -OSO2R ⁸ , -OCONR ⁸ R ⁹ , NR ⁸ COOR ⁹ , -NR ⁸ COR ⁹ , -NR ⁸ R ⁹ , -NR ⁸ SO2R ⁹ , -NR ⁸ CONR ⁹ R ¹⁰ , -NR ⁸ CSNR ⁸ R ⁹ , -SO ₂ R ⁸ , -SOR ⁸ , -SR ⁸ , -SO2NR ⁸ R ⁹ , -SO2OR ⁸ , -COOR ⁹ , -COR ⁹ , -CONR ⁸ R ⁹ , where R ⁸ , R ⁹ and R ¹⁰ are independently hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; when R ⁸ and R ⁹ are on a nitrogen atom, they can together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms;

m is an integer from 0 to 6;

n is an integer from 0 to 6.

The present invention also relates to a process for preparing the above-mentioned compounds, their derivatives, analogues, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and compositions containing the aforementioned.

The present invention also relates to novel intermediates, their preparation processes, their use in the preparation processes of the compounds of general formula (I), and their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic agents.

The compounds of the present invention reduce plasma glucose, triglyceride, insulin, total cholesterol (TC), increase high-density lipoprotein (HDL) and reduce low-density lipoprotein (LDL) concentrations, all of which have beneficial effects on coronary heart disease and atherosclerosis.

The compounds of formula (I) are useful for reducing body weight and for preventing and/or treating atherosclerosis, stroke, peripheral vascular disease and disorders related thereto. These compounds can be used to treat hyperlipidemia, hyperglycemia, hypercholesterolemia, and to reduce atherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL levels. The compounds of the present invention can be used to treat kidney diseases such as glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. The compounds of formula (I) can also be used to treat and/or prevent leptin resistance, impaired glucose tolerance, θζ X syndrome-related disorders such as hypertension, obesity, insulin resistance, coronary artery disease and other cardiovascular disorders. These compounds can be used as aldose reductase inhibitors, improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), inflammatory diseases, and other conditions.

I·.’.::.·::· .··’ inflammatory bowel disease, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, eating disorders, inflammation and cancer. The compounds of the present invention are also used for the treatment and/or prevention of the above-mentioned diseases in combination with one or more HMG CoA reductase inhibitors, cholesterol uptake inhibitors, anti-obesity agents, agents for the treatment of lipoprotein disorders, hypoglycemic agents, insulin, biguanides, sulfonylureas, thiazolidinediones, dual PPARα and γ agonists or mixtures thereof.

Atherosclerosis and other peripheral vascular diseases affect the quality of life of millions of people, therefore, there is great interest in the etiology of hypercholesterolemia and hyperlipidemia and in the development of treatments for these diseases.

Hypercholesterolemia is defined as plasma cholesterol levels exceeding the accepted normal range. It is currently accepted that the ideal plasma cholesterol level is well below the normal range in the population, and the risk of coronary artery disease (CAD) increases as cholesterol levels rise above the optimal (or ideal) level. There is a well-established causal relationship between hypercholesterolemia and CAD, particularly in individuals with multiple risk factors. Most cholesterol is present in esterified form with various lipoproteins, such as low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), high-density lipoprotein (HDL), and especially very-low-density lipoprotein (VLDL). Studies clearly indicate that CAD and atherosclerosis are inversely related to serum HDL cholesterol concentrations [Stampfer et al., N. Eng. J. Med., 325:378-391 (1991)]. The risk of CAD increases with increasing LDL and VLDL levels.

I ► 6 :·'

In CAD, fatty streaks are usually present in the coronary arteries, the coronary arteries, and the cerebral arteries, which are mainly composed of free and esterified cholesterol. Miller et al. [Br. Med. J., 282:1741-1744 (1981)] have shown that increasing the number of HDL particles can reduce the number of narrowings (stenoses) in the coronary arteries in humans and that high HDL cholesterol levels may provide protection against the development of atherosclerosis. Ricardo et al. [Arteriosclerosis, 6:434-441 (1986)] have demonstrated in vitro that HDL can remove cholesterol from cells. It is hypothesized that HDL can remove excess cholesterol from tissues and transport it to the liver, a process known as reverse cholesterol transport [Macikinnon et al., J. Biol. Chem., 261:2548-2552 (1986)]. Thus, agents that increase HDL cholesterol levels are of therapeutic importance in the treatment of hypercholesterolemia and coronary heart disease (CHD).

Obesity is very common in affluent societies and the developing world, and is a major cause of morbidity and mortality. It is the accumulation of excess body fat. The cause of obesity is unknown. It is thought to be genetic in origin or to be facilitated by the interaction of genotype and environment. Regardless of the cause, the result is fat accumulation, which is the result of an imbalance between energy intake and energy expenditure. Diet, exercise, and appetite control are part of the treatment of obesity. Effective treatment is urgently needed to combat this disease, as obesity can lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoporosis, reduced fertility, and many other psychological and social problems.

Diabetes and/or insulin resistance is another disease that seriously affects a large part of the world's population. In insulin resistance, the ability of insulin to exert its biological action over a wide range of concentrations is reduced. In insulin resistance, the body produces abnormally large amounts of insulin to compensate for the lack of effect; this imperfection inevitably leads to an increase in plasma glucose concentration and the development of diabetes mellitus. Diabetes is a common problem in developed countries and is associated with a variety of disorders, including obesity, hypertension, and hyperlipidemia [J. Clin. Invest., 75:809-817 (1985); N.Engl. J. Med., 317:350-357 (1987); J. Clin. Endocrinol. Metab., 66:580-833 (1985); J. Clin. Invest., 68:957-969 (1975)] and renal complications (Patent Publication No. WO 95/21608). There is increasing recognition that insulin resistance and relative hyperinsulinemia contribute to the development of obesity, hypertension, atherosclerosis, and type 2 diabetes. The association of insulin resistance with obesity, hypertension, and angina has been described as a syndrome in which insulin resistance is a central pathogenic link in Syndrome X.

Hyperlipidemia is a primary cause of cardiovascular (CVD) and other peripheral vascular diseases. The risk of CVD is related to the higher LDL and VLDL levels seen in hyperlipidemia. Patients with hyperlipidemia, in addition to impaired glucose tolerance and insulin resistance, are at increased risk of CVD. Several studies have demonstrated that lowering plasma triglycerides and total cholesterol levels, especially LDL and VLDS, and raising HDL cholesterol levels help prevent CVD.

Peroxisome proliferator-activated receptors (PPARs) are orphan receptors that belong to the steroid/retinoid receptor superfamily of ligand-activated transcription factors [Wilson T. M. and Wahli W., Curr. Opin. Chem. Biol., Vol. 1, 235-241, (1997)]. Three PPARs have been isolated in mammals, designated PPAR-α, PPAR-β and PPAR-δ. These PPARs regulate the expression of target genes by binding to DNA sequence elements.

Certain chemicals that activate or otherwise interact with one or more PPARs have been implicated in the regulation of triglyceride and cholesterol levels in animal models (U.S. Patents 5,847,008, 5,859,051, PCT Patent Publications WO 97/28149, WO 99/04815).

There is ample information available on the effects of PPAR-α agonists on cardiovascular disease, such as fibrates, which are weak PPAR-α agonists and improve atherogenic dyslipoproteinemia. Several angiographic studies have demonstrated that these agents have a beneficial effect on the development of atherosclerotic lesions, and primary and secondary prevention studies have shown that they reduce the incidence of cardiovascular events [Ricote M. and Glas C. K., Trends in Pharmacological Sciences, 22(9): 441-443 (2001)].

Although fibrates, which are weak PPAR-α activators, reduce plasma triglycerides and simultaneously increase HDL cholesterol levels, they are not used as drugs because their low efficacy would require high doses, they cause muscle inflammation (myositis) and their use is contraindicated in patients with renal and hepatic insufficiency, as well as in pregnant and lactating mothers.

However, great progress has been made in understanding the role of PPAR-α in various pathophysiological conditions, in addition to the well-documented beneficial effects it has on the lipid profile. The inflammatory activation of aortic smooth muscle cells, a hallmark of atherosclerosis, appears to be inhibited by increased PPAR-α activity [Vamecq J. and Latruffe N., Lancet, 354:141-148 (1999)].

Recent data suggest that PPAR-α receptors play a role in improving insulin sensitivity. PPAR-α ligands have been shown to improve insulin sensitivity and reduce obesity by reducing circulating and muscle lipids in rodent models of insulin resistance, such as obese Zucker rats, high-fat-fed mice, and sucrose-fed rats. Furthermore, the lipid-lowering activity of statins is related to crosstalk with the PPAR-α receptor, in addition to their cholesterol-lowering properties. Some clinical trials with fibrates have shown improvements in insulin sensitivity [Guerre-Millo M., Rounalt C., and Poulain P., Diabetes, 50:2809-2814 (2001); Muoio DM, Way JM, and Tanner CJ, Diabetes 51:901-909 (2002); Ye J, Doyle PJ and Iglesias MA, Diabetes 50:411-417 (2001); Roglans N., Sanguine E. and Peris C. JPET, 302:232-239 (2002)].

It is therefore of interest that PPAR-α agonists are useful in regulating lipids and, according to current evidence, in influencing insulin resistance. The limitations of currently available drugs, coupled with the fact that the number of lipid disorders is increasing worldwide, necessitates the discovery of more effective and safer PPAR-α agonists. In the course of our research work on PPAR agonists (U.S. Patents 5,885,997, 6,054,453, 6,265,401, PCT Application No. PCT/IB02/04275), we have prepared a series of compounds that are discussed in the present invention.

Several alkyl carboxylic acids, their derivatives and analogues have been described as being useful in the treatment of hyperglycemia and hypercholesterolemia. Some of these are described below:

(i) U.S. Patent No. 5,306,726, WO 91/19702 disclose some 3-aryl-2-hydroxypropanoic acid derivatives of the general formulae (IIa) and (IIb) as hypolipidemic and hypoglycemic agents. Examples of these compounds are compounds of the formulae (IIe) and (IId).

► (ιι) International patent publications WO 95/03038 and WO 96/04260 deal with compounds of general formula (He), an example of which is the compound of formula (llf).

(iii) International Patent Publications WO 94/13650, WO 94/01420 and WO 95/17394 disclose compounds of formula (IIg), exemplified by compound (Uh).

(iv) International Patent Publication No. WO 00/49005 describes compounds of formula (III), exemplified by compound (IIj). (v) International Patent Publication No. WO 94/12181 discloses compounds of formula (IIk), exemplified by compound (IIt).

(vi) International Patent Publication No. WO 93/16697 and United States Patent No. 5,227,490 disclose compounds of the general formula (Hm), exemplified by the compound of the formula (Un).

(vii) International Patent Publication No. WO 99/62871 discloses compounds of formula (llo) wherein A is a group of formula (a) or (b) which may be attached in the ortho, meta or para position. An example of such compounds is the compound of formula (llp).

(viii) International Patent Publication No. WO 00/64888 discloses compounds of formula (IIq), exemplified by compound (IIr).

(ix) WO 99/62872 describes compounds of formula (IIs).

(x) International Patent Publication No. WO 00/63153 discloses compounds of formula (lit), exemplified by compound (Hu).

(Xi) International Patent Publication No. WO 01/55085 relates to compounds of formula (IIv), exemplified by the compound of formula (IIw).

Several β-phenyl-α-hydroxypropionic acid derivatives have been described, which can be used as intermediates in the preparation of the target compounds. Some of them are described below.

(i) European Patent Application EP0816316 relates to compounds of formula (Va). Compounds of formula (Va) are further converted to 1,2-ethanediol derivatives of formula (Vb). These ethanediol derivatives are useful intermediates in the production of pharmaceuticals and agricultural chemicals.

(ii) Japanese Patent Application No. JP 10017540 discloses a compound of formula (Ve). This compound is further converted to a compound of formula (Vd).

The present invention relates to compounds of general formula (I) which, having mainly PPAR-a agonist activity and showing a markedly reduced toxicity related to PPAR-γ activity, reduce blood sugar, lipids and cholesterol levels and body weight, exerting a beneficial effect in the treatment and/or prevention of diseases associated with elevated lipid levels, atherosclerosis, coronary artery disease, syndrome X, impaired glucose tolerance, insulin resistance, insulin resistance leading to type 2 diabetes and complications associated with diabetes, in the treatment of diseases where insulin resistance is the pathophysiological mechanism, and in the treatment of hypertension. The compounds of the invention are more effective and have lower toxicity. Our quest to develop new compounds useful for the effective treatment of said diseases led us to the compounds of general formula (I).

The main aspect of the present invention is therefore to provide novel compounds of general formula (I), their derivatives, analogues, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and compositions containing the same.

Another aspect of the present invention is to provide novel alkyl carboxylic acids, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and compositions containing the same, which have agonist activity at PPAR-α and/or PPAR-γ receptors and optionally inhibit HMG CoA reductase in addition to their PPAR-α and/or PPAR-γ agonist activity.

A further aspect of the present invention is to provide a process for the preparation of alkyl carboxylic acids of formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and compositions containing the same.

A further aspect of the present invention is to provide pharmaceutical compositions comprising as active ingredients the compounds of formula (I), their analogues, derivatives, tautomers, stereoisomers, polymorphs, salts, solvates or mixtures thereof, together with a suitable carrier, solvent, diluent and other commonly used media.

A further aspect of the present invention is to provide novel intermediates, processes for their preparation and their use in the preparation of compounds of general formula (I), their derivatives, analogues, tautomers, stereoisomers, and their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic agents.

The novel β-aryloxy-substituted propanoic acids are the compounds described by the general formula (I), their derivatives, analogues, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates.

In general formula (I)

R ¹ represents hydrogen, halogen, hydroxyl, straight or branched alkyl having 1-12 carbon atoms, straight or branched alkoxy having 1-12 carbon atoms, 1-13 carbon alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl or forms a bond together with the adjacent R ² group;

R ² represents hydrogen, halogen, straight or branched C 1-12 alkyl, straight or branched C 1-12 alkoxy, C 1-12 alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl or R ² together with R ¹ forms a bond;

R ³ represents a hydrogen atom, a substituted or unsubstituted group: a straight or branched, C 1-12 alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, C 1-12 alkanoyl, aroyl, arylalkyl, arylalkanoyl, heterocyclic, heteroaryl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl or arylaminocarbonyl group;

R ⁴ represents a hydrogen atom, a straight or branched C 1-12 alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic, heteroaryl or heteroarylalkyl group;

Y represents an oxygen atom, a group of the general formula NR ⁷ or N(R ⁷ )O, where R ⁷ represents a hydrogen atom or a substituted or unsubstituted group: a straight or branched, C 1-12 alkyl, aryl, arylalkyl, hydroxyalkyl, alkanoyl, aroyl, arylalkanoyl, heterocyclic, heteroaryl, heteroarylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group;

R ⁴ and R ⁷ together may form a saturated or unsaturated 5-6 membered ring structure consisting of carbon atoms and nitrogen atoms, and optionally containing one or more additional heteroatoms, namely oxygen, sulfur or nitrogen atoms;

R ⁵ represents a hydrogen atom or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aroyl or aralkanoyl group;

Ar represents a substituted or unsubstituted divalent group of the following: phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolyl, pyrazolyl, benzothiazolyl, benzoxazolyl or the like;

X is -C(=O)-, -C(=S)-, -C(=S)-O-, -0(=0)-0-, -C(=O)-S-, -0-(CH ₂ ) _d -, -NH-(CH ₂ ) _d -, -0-0(=0)-, -C(=O)CH ₂ -, -CR ^a =CR ^b -CH ₂ -, -CR ^a =CR ^b -CO- or a group of the general formula, wherein R ^a and R ^b independently represent a hydrogen atom or an alkyl group having 1-6 carbon atoms, d represents an integer of 1-4; or X represents a bond;

R ⁶ is a substituted or unsubstituted group: aryloxycarbonyl, arylalkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl-(Fmoc), fluorenylmethoxycarbonylamino-(N-Fmoc), -OSO 2 R 8 , -OCONR 8 R 9 , NR 8 COOR 9 , -NR 8 COR ⁹ , -NR ⁸ SO2R ⁹ , -NR 8 CONR ₉ R 10 , -NR ⁸ CSNR ⁸ R ⁹ , ^{-SO2R 8 , -SOR 8 ,} -SR ⁸ , -SO2NR ^{8 R 9 , -SO2OR 8} , ^{-COOR 9 , -COR 9 or -CONR 8 R 9 general} a group of formula wherein R ⁸ , R ⁹ and R ¹⁰ are independently hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; when R ⁸ and R ⁹ are on a nitrogen atom, they may together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms; R ⁶ is hydrogen when R ¹³ is at the 3-position of the phenyl ring and is not hydrogen;

R ¹³ is hydrogen, halogen, nitro, cyano, amino, halogenated alkyl, hydroxyl or the following groups, substituted or unsubstituted: straight or branched, C1-C12 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryl-oχι-, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl-(Fmoc), fluorenylmethoxycarbonylamino-(N-Fmoc), -OSO2R ⁸ , -OCONR ⁸ R ⁹ , NR ⁸ COOR ⁹ , -NR ⁸ COR ⁹ , -NR ⁸ R ⁹ , -NR ⁸ SO2R ⁹ , -NR ⁸ CONR ⁹ R ¹⁰ , -NR ⁸ CSNR ⁸ R ⁹ , -SO ₂ R ⁸ , -SOR ⁸ , -SR ⁸ ,

a group of the general formula -SO ₂ NR ⁸ R ⁹ , -SO2OR ⁸ , -COOR ⁹ , -COR ⁹ , -CONR ⁸ R ⁹ , where R ⁸ , R ⁹ and R ¹⁰ independently represent a hydrogen atom or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; when R ⁸ and R ⁹ are on a nitrogen atom, they can together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms;

m is an integer from 0 to 6;

n is an integer from 0 to 6.

Suitable R ¹ groups are selected from the following: hydrogen, hydroxyl, halogen, straight or branched alkyl groups having 1-12 carbon atoms, preferably 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl or tert-butyl; straight or branched alkoxy groups having 1-12 carbon atoms, preferably 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and the like; substituted or unsubstituted arylalkyl groups such as benzyl, phenethyl and the like; or R ¹ together with R ² forms a bond. The arylalkyl group may be substituted with 1-6 carbon alkyl, 1-6 carbon alkoxy or hydroxyl.

Suitable ^R2 groups can be selected from the following: hydrogen, hydroxyl, halogen, straight or branched alkyl groups having 1-12 carbon atoms, preferably 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl or tert-butyl; straight or branched alkoxy groups having 1-12 carbon atoms, preferably 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and the like; alkanoyl groups having 1-12 carbon atoms, such as acetyl, propanoyl, butanoyl, pentanoyl and the like; aroyl groups such as benzoyl and the like; arylalkanoyl groups such as phenylacetyl, phenylpropanoate and the like; substituted or unsubstituted arylalkyl groups such as benzyl, phenethyl and the like; or R ² may form a bond with R ^1. The aryl-alkyl

-group may be substituted with C1-6 alkyl, C1-6 alkoxy or hydroxyl.

Suitable R ³ groups can be selected from the following: hydrogen, substituted or unsubstituted, straight or branched, C 1-12 alkyl groups, such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; substituted or unsubstituted, C 1-12, preferably C 2-8 alkanoyl groups, such as acetyl, propanoyl, butanoyl, pentanoyl and the like; aroyl groups, such as benzoyl and the like, which may be substituted; arylalkanoyl groups, such as phenylacetyl, phenylpropanoyl and the like, which may be substituted; cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; C3-7 cycloalkylalkyl group, such as cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl and the like, which may be substituted; C3-7 cycloalkenyl group, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like, the cycloalkenyl group may be substituted; aryl group, such as phenyl, naphthyl and the like, the aryl group may be substituted; arylalkyl group, such as benzyl, phenethyl, C6H5CH2CH2CH2, naphthylmethyl and the like, the arylalkyl group may be substituted; heterocyclic group, such as aziridinyl, pyrrolidinyl, piperidinyl and the like; the heterocyclic group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl and the like, the heteroaryl group may be substituted; heteroaryl alkyl group such as furanmethyl, pyridinemethyl, oxazolmethyl, oxazolethyl and the like, the heteroalkyl alkyl group may be substituted; C1-6 alkoxy-(C1-6)alkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropyl and the like, the alkoxy alkyl group may be substituted; C1-6 alkoxycarbonyl, propoxycarbonyl and the like, which may be substituted; aryloxycarbonyl group such as phenoxycarbonyl, naphthyloxycarbonyl and the like, which may be substituted; C1-6 alkylaminocarbonyl group such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and the like, which may be substituted; and arylaminocarbonyl group such as PhNHCO, naphthylaminocarbonyl and the like, which may be substituted. The substituents of R ³ may be selected from the following: halogen atom, hydroxyl, cyano, nitro group or substituted or unsubstituted alkyl, cycloalkyl, alkoxy, cycloalkoxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like; aryl alkoxy alkyl group such as benzyloxy-CH ₂ -, benzyloxy-CH ₂ -CH ₂ -, naphthyloxy-CH ₂ -, 2-phenethyloxy-CH ₂ - and the like; aryl, arylalkyl, heterocyclic, heteroaryl, heteroarylalkyl, acyl, acyloxy group such as OCOMe, OCOEt, OCOPh and the like; hydroxyalkyl, amino, acylamino group such as NHCOCH ₃ , NHCOC ₂ H ₅ and the like; arylamino group such as _{HNC 6} H ₅ , NCH( _CH aminoalkyl, aryl-oχι-, alkoxycarbonyl, alkylamino group such as NHCH ₃ , NHC ₂ H ₅ , NHC3H7, N(CH ₃ ) ₂ , NCH ₃ (C ₂ H ₅ ), N(C ₂ H ₅ ) ₂ and the like; alkoxyalkyl, alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio group and the like; thioalkyl group such as thiomethyl, thioethyl, thiopropyl group and the like, carboxylic acid group and derivatives thereof; sulfonic acid group and derivatives thereof. The derivative of carboxylic acid and sulfonic acid may be amide, chloride, ester and anhydride.

Suitable R ⁴ groups can be selected from the following: hydrogen, substituted or unsubstituted, straight or branched, C 1-12 alkyl groups, such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, pentyl, hexyl, heptyl, octyl and the like; C 3-7 cycloalkyl groups, such as cyclopropyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl groups, such as phenyl, naphthyl and the like, the aryl group may be substituted; arylalkyl groups, such as benzyl, phenethyl, the arylalkyl group may be substituted; heterocyclic groups, such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclic group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl and the like, the heteroaryl group may be substituted; heteroaryl alkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl and the like, the heteroaryl alkyl group may be substituted. The substituents of R ⁴ are selected from the following: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like; aryl alkoxy alkyl group such as benzyloxy-CH ₂ -, benzyloxy-CH ₂ -CH ₂ -, naphthyloxy-CH ₂ -, 2-phenethyloxy-CH ₂ - and the like; aryl, arylalkyl, heterocyclic, heteroaryl, heteroarylalkyl, acyl, acyloxy groups such as OCOMe, OCOEt, OCOPh and the like; hydroxyalkyl, amino, acylamino groups such as NHCOCH ₃ , NHCOC ₂ H ₅ and the like; arylamino groups such as HNCeHs, NCH^CgHs), NHC6H4CH3, NHCeH^Hal and the like; aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino groups such as NHCH3, NHC ₂ Hs, NHC3H7, N(CH ₃ ) ₂ , NCH ₃ (C ₂ H ₅ ), N(C ₂ Hs) ₂ and the like; alkoxyalkyl, alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio and the like; thioalkyl group such as thiomethyl, thioethyl, thiopropyl and the like, carboxylic acid group and derivatives thereof; sulfonic acid group and derivatives thereof.

Suitable R ⁵ groups may be selected from the following: hydrogen, substituted or unsubstituted, straight or branched, C 1-16 alkyl groups, preferably C 1-12 alkyl groups, such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, pentyl, hexyl, heptyl, octyl and the like; substituted or unsubstituted, straight or branched, C 2-8 alkenyl groups, such as ethenyl, n-propenyl, η-butenyl, isobutenyl, n-pentenyl, hexenyl, heptenyl and the like; cycloalkyl groups having C 3-7 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; C3-7 cycloalkyl-(C1-C10)alkyl group, such as cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl and the like; which may be substituted; aryl group, such as phenyl, naphthyl and the like; the aryl group may _be substituted; arylalkyl group, such as benzyl, _phenethyl , _{C6H5CH2CH2CH2 , naphthylmethyl} and the like, the arylalkyl group may be substituted; aroyl group, such as benzoyl and the like, which may be substituted; aralkanoyl group, such as phenylacetyl, phenylpropanoyl and the like, which may be substituted. The substituent of the R ⁵ group may be a halogen atom, a hydroxyl, nitro, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl, arylalkoxyalkyl group, such as the group of formula C ₆ H ₅ CH ₂ OCH2-, C ₆ H ₅ CH ₂ OCH ₂ CH-, C6 H ₅ -CH ₂ CH ₂ OCH ₂ CH ₂ -, Ο6Η5Η ₂ ΟΗ ₂ ΟΟΗ ₂ - and the like; heterocyclic, heteroaryl and amino groups.

Suitable R ⁵ groups may be selected from the following: unsubstituted or substituted aryloxycarbonyl groups such as phenoxycarbonyl, naphthyloxycarbonyl and the like; arylalkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; alkylcarbonyloxy groups such as methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy and the like, which may be substituted; alkoxycarbonylamino groups such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino and the like, which may be substituted; aryloxycarbonylamino group such as NHCOOC ₆ H ₅ , N(CH ₃ )COOC ₆ H ₅ , N(CH ₂ H ₅ )COOC ₆ H ₅ , NHCOOC ₆ H ₄ CH ₃ , NHCOOC ₆ H ₄ OCH ₃ and the like, which may be substituted; arylalkoxycarbonylamino group such as NHCOOCH ₂ C ₆ H ₅ , NHCOOCH ₂ CH ₂ C 6 H 5 , N(CH ₃ )COOCH ₂ C ₆ H _{5 ,} N(C ₂ H _{5 )} COOCH ₂ C ₆ H ₅ ,

HCOOCH2C5H4CH3, NHCOOCH2C6H4OCH3 and the like; which may be substituted; fluorenylmethoxycarbonyl-(Fmoc), fluorenylmethoxycarbonyl(N-Fmoc), -OSO2R ⁸ , -OCONR ⁸ R ⁹ , -NR 8 COOR 9 , -NR ⁸ COR ⁹ , -NR ⁸ SO ₂ R ⁹ , -NR ⁸ CONR ⁹ R ¹⁰ , -NR ⁸ CSNR ⁸ R ⁹ , -SO2R ⁸ , ^{-SOR 8} , -SR ⁸ , -SO2NR ⁸ R ⁹ , -SO2OR ⁸ , -COOR ⁹ , -COR ⁹ or -CONR ⁸ R ^{9 . R 6 is} hydrogen when R ¹³ is at the 3-position of the phenyl ring and is not hydrogen.

When R ⁶ is substituted, the substituent may be a halogen atom, hydroxyl, nitro, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl or amino group.

Suitable R ¹³ groups can be selected from the following: hydrogen atom, halogen atom, such as fluorine, chlorine, bromine or iodine atom; hydroxyl, amino, nitro, cyano group, unsubstituted or substituted, straight or branched, C 1-12 alkyl group, such as methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl group and the like; halogenated alkyl group, such as trifluoromethyl group and the like; C 1-6 alkoxy group, such as methoxy, ethoxy, propoxy group and the like, which may be substituted; aryl group, such as phenyl, naphthyl group and the like, the aryl group may be substituted; arylalkyl group such as benzyl, phenethyl, C ₆ H ₅ CH ₂ CH ₂ CH ₂ , naphthylmethyl group and the like, the arylalkyl group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl group and the like, the heteroaryl group may be substituted; heteroarylalkyl group such as furanmethyl, pyridinemethyl, oxazolmethyl, oxazolethyl group and the like, the heteroarylalkyl group may be substituted; heterocyclic group such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl group and the like, the heterocyclic group may be substituted; monoalkylamino group such as NHCH ₃ , NHC2H5 , NHC3H7 , NHC _6H13 and the like, which may be substituted; dialkylamino group such as N ₍ CH ₃ ) ₂ , NHCH ₃ (C ₂ H5 ), N(C _{2 H5} ) ₂ and the like, which may be substituted; alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like, which may be substituted; aryloxycarbonyl group such as phenoxycarbonyl, naphthyloxycarbonyl and the like, which may be substituted; aryl alkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; aryl oxy group such as phenoxy, naphthyloxy and the like, the aryl oxy group may be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; aryl oxy group such as phenoxy, naphthyloxy and the like, the aryl oxy group may be substituted; aryl alkoxy group such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, the aryl alkoxy group may be substituted; alkylcarbonyloxy group such as methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy and the like, which may be substituted; alkoxycarbonylamino group such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino and the like, which may be substituted; aryloxycarbonylamino group such as NHCOOC ₆ H ₅ , N(CH ₃ )COOC ₆ H ₅ , N^HLHsjCOOCsHs.NHCOOCgHLCHa, NHCOOC6H4OCH3 and the like, which may be substituted; aryl-alkoxycarbonylamino groups such as NHCOOCH ₂ C ₆ H ₅ , NHCOOCH ₂ CH ₂ C ₆ H ₅ , N(CH ₃ )COOCH ₂ C 6 H 5 , N(C ₂ H ₅ )COOCH _{2 C6 H5} , NHCOOCH ₂ C5H4CH ₃ , NHCOOCH ₂ C ₆ H ₄ OCH ₃ and the like; which may be substituted; fluorenylmethoxycarbonyl-(Fmoc), fluorenylmethoxycarbonyl-(N-Fmoc), -OSO ₂ R 8 , -OCONR ⁸ R ⁹ , -NR 8 COOR ⁹ , -NR ⁸ COR ⁹ , -NR ⁸ R 9 , -NR ⁸ SO2R ⁹ , -NR ⁸ CONR ⁹ R ¹⁰ , -NR ⁸ CSNR ⁸ R ⁹ , -SO2R ⁸ , -SOR ⁸ , -SR ⁸ , -SO2NR ⁸ R ⁹ , -SO2OR ⁸ , -COOR ⁹ , -COR ⁹ or -CONR ^{8 R 9 group of} the general formula.

When R ¹³ is substituted, the substituent may be a halogen atom, hydroxyl, nitro, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl or amino group.

Suitable R ⁸ , R ⁹ , R ¹⁰ groups can be selected from the following: hydrogen atom, unsubstituted, straight or branched, C 1-12 alkyl group, such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl group and the like; aryl group, such as phenyl, naphthyl group and the like, the aryl group may be substituted; arylalkyl group, such as benzyl, phenethyl, C _s H ₅ CH2CH ₂ CH2, naphthylmethyl group and the like, the arylalkyl group may be substituted; alkoxycarbonyl group, such as tert-butyloxycarbonyl group (BOC) and the like; arylalkoxycarbonyl group, such as benzyloxycarbonyl group (CBz) and the like. When R ⁸ and R ⁹ are on a nitrogen atom, they may together form a 5- or 6-membered ring system consisting of carbon atoms and at least one nitrogen atom, optionally one or more heteroatoms which may be oxygen, sulfur or nitrogen atoms, and the ring system may contain one or two double bonds or may be aromatic. The substituents of R ⁸ , R ⁹ and R ¹⁰ may be halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, cycloalkyl, aryl, arylalkyl, acyl, acyloxy, hydroxyalkyl, amino, aryloxy, alkylthio or thioalkyl.

Suitable R ⁷ groups can be selected from the following: hydrogen, substituted or unsubstituted, straight or branched, C 1-12 alkyl; aryl, such as phenyl, naphthyl and the like, the aryl group may be substituted; hydroxyalkyl, having 1-6 carbon atoms, which may be substituted; arylalkyl, such as benzyl and phenethyl and the like, which may be substituted; heterocyclic, such as aziridinyl, pyrrolidinyl, piperidinyl and the like, which may be substituted; heteroaryl, such as pyridyl, thienyl, furyl and the like, which may be substituted; heteroarylalkyl, such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl and the like, which may be substituted; a straight or branched C2-C8 alkanoyl group such as acetyl, propanoyl, butanoyl, pentanoyl and the like, which may be substituted; an aroyl group such as benzoyl and the like, which may be substituted; an arylalkanoyl group such as phenylacetyl, phenylpropanoyl and the like, which may be substituted; an alkoxycarbonyl group such as tert-butyloxycarbonyl and the like; an arylalkoxycarbonyl group such as benzyloxycarbonyl and the like. The substituent R ⁷ may be a halogen atom, hydroxyl, alkoxy, cyano, nitro, alkyl, cycloalkyl, aryl, arylalkyl, acyl, acyloxy, hydroxyalkyl, amino, aryloxy, alkylthio or thioalkyl group.

The ring structure formed by R ⁴ and R ⁷ may be pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolinyl and the like.

Suitable Ar groups may be selected from the following: substituted or unsubstituted divalent phenylene, naphthylene, benzofuryl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups, which may be optionally substituted with alkyl, halogenated alkyl, methoxy or halogenated alkoxy groups.

n and m are integers from 0 to 6.

Suitable X is a group of the formula -C(=O)-, -O(CH ₂ ) _d (where d is an integer of 1-4), -C(=S)-, -OC(=O)-, -C(O)CH 2 -, -CH=CH-CH ₂ -, -CH=CH-CO- or X is a bond.

Preferred compounds of formula (I) are those wherein:

R ¹ represents a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms or forms a bond with R ² ;

R ² represents a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms or forms a bond with R ¹ ;

R ³ represents a hydrogen atom, a straight or branched C 1-12 alkyl, C 3-7 cycloalkyl, aryl group such as phenyl, naphthyl or arylalkyl;

R ⁴ represents a hydrogen atom, a straight or branched C 1-12 alkyl, C 3-7 cycloalkyl, aryl such as phenyl, naphthyl or arylalkyl;

R ⁵ represents a hydrogen atom, a C 1-12 alkyl group or a C 3-7 cycloalkyl group;

R ⁶ is a fluorenylmethoxycarbonyl group (Fmoc), a fluorenylmethoxycarbonylamino group (N-Fmoc), a group of the general formula -OSO ₂ R ⁸ , -OCONR ⁸ R ⁹ , NR ⁸ COOR ⁹ , -NR ⁸ COR ⁹ or -NR ⁸ SO 2 R ⁹ ;

R ⁸ represents a hydrogen atom, a straight or branched C 1-6 alkyl group or an aryl group, optionally substituted;

R ⁹ represents a hydrogen atom, a straight or branched C 1-6 alkyl group, tert-butyloxycarbonyl or benzyloxycarbonyl group;

R ¹³ represents a hydrogen atom or a group of the general formula -OSO ₂ R ⁸ ;

X is a group of the formula -C(=O)-, -OC(=O)-, -O(CH3)d- (where d is an integer of 1-4), -C(=S)-, -CH=CH- _CH2- , -CH=CH-CO- or X is a bond;

Y represents an oxygen atom or a group of the general formula NR ⁷ ;

R ⁷ represents a hydrogen atom, a substituted or unsubstituted, straight or branched, C 1-12 alkyl group, an optionally substituted aryl group;

d is an integer from 1 to 4;

m is 0 or 1;

n is an integer from 0 to 2.

Even more preferred are those compounds of general formula (I) wherein

R ¹ is hydrogen or R ¹ forms a bond with R ² ;

R ² represents a hydrogen atom or R ² forms a bond with R ¹ ;

R represents a hydrogen atom, a straight or branched chain alkyl group having 1 to 12 carbon atoms;

R ⁴ represents a hydrogen atom, a straight or branched chain alkyl group having 1 to 12 carbon atoms;

R ⁵ represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms;

R ⁶ is a group of the general formula -OSO 2 R 8 or -NR ⁸ SC>2 R ⁹ ;

R represents a straight or branched C1-6 alkyl group or a substituted aryl group, wherein the substituent is a straight or branched C1-6 alkyl group;

R ⁹ is a straight or branched C 1-6 alkyl, tert-butyloxycarbonyl or benzyloxycarbonyl group;

R ¹³ represents a hydrogen atom or a group of the general formula -OSO ₂ R ⁸ ;

X is a group of the general formula -C(-O)-, -O-C(=O)-, -O(CH2)d- (where d is an integer of 1-4), -CH-CH-CH2-, -CH=CH-CO- or X is a bond;

Y represents an oxygen atom.

Pharmaceutically acceptable salts forming part of the present invention include salts formed with inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn salts; salts formed with organic bases, where the organic base is, for example, Ν,Ν'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, theobromine, valinol, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamantylamine, diethanolamine, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, Ν,Ν'-dibenzylethylenediamine, N-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine and the like; chiral bases such as alkylphenylamine, glycinol, phenylglycinol and the like; salts of natural amino acids such as the amino acids glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; salts of unnatural amino acids such as the D-isomers or substituted ones; salts of acidic amino acids such as aspartic acid, glutamic acid; salts of guanidine or guanidine substituted with nitro-, amino-, alkyl-, alkenyl-, alkynyl groups; salts of ammonium and substituted ammonium. The salts may be acid addition salts, which may be sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides (HCl, HBr, Hl), acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates are hydrates or solvates formed with the solvents in which the crystallization occurred, e.g. alcoholates.

Particularly suitable compounds according to the present invention are: ethyl-[2-methoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propyloxycarbonylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionate], ethyl-[2-isopropoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]-phenyl}-propionate], methyl-[2-ethoxy-3-[4-(4-methanesulfonyloxybenzylamino)-phenyl]-propionate],

2-Methoxy-3-[4-{3-(4-methanesulfonyloxy-phenyl)-propyl-amino}-phenyl]-propionic acid, 2-Ethoxy-3-[4-{3-(4-methanesulfonyl-oxy-phenyl)-propyl-amino}-phenyl]-propionic acid, 2-Ethoxy-3-[4-{3-(4-methanesulfonyl-oxy-phenyl)-propyl-oxy-carbonyl-amino}-phenyl]-propionic acid,

2-ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionic acid, 2-ethoxy-3-[4-{3-(4-(toluene-4-sulfonyloxy)-phenyl)-propylamino}-phenyl]-propionate, 2-ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionic acid, 2-isopropoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionic acid,

2-ethoxy-3-[4-(4-methanesulfonyloxybenzylamino)phenyl]propionic acid,

2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propionic acid,

2-Ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)propenylamino}phenyl]propionic acid, ethyl [2-ethoxy-3-[4-(4-methylsulfonyloxybenzylcarboxamido)phenyl]propionate], 2-Ethoxy-3-[4-(4-methylsulfonyloxybenzylcarboxamido)phenyl]propionic acid, ethyl [2-ethoxy-3-[4-(3-tert-butoxy-4-methylsulfonamidophenyl)propylamino}phenylpropionate],

2-Ethoxy-3-[4-{3-(4-tert-butoxy-4-methylsulfonamidophenyl)propylamino}phenyl]propionic acid, ethyl [2-ethoxy-3-{4-[(E)-2-(4-methylsulfonyloxyphenyl)-1-ethenylcarboxamido]phenyl}propionate],

2-Ethoxy-3-{4-[(E)-2-(4-methylsulfonyloxyphenyl)-1-ethenylcarboxamido]phenyl}-propionic acid, ethyl [2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylcarboxamido)phenyl]propionate],

2-ethoxy-3-[4-(4-methylsulfonyloxyphenethenylcarboxamido)phenyl]propanoic acid, ethyl [2-methoxy-3-[4-{(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino}phenyl]propionate],

2-methoxy-3-[4-{(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino}-phenyl]-propionic acid, ethyl [2-methoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propanoate],

2-methoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionic acid, ethyl [2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamido]-phenyl}-propanoate],

2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamido]-phenyl}-propionic acid, methyl [2-methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamido]-phenyl}-propanoate],

2-Methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]enyl}-propanoic acid or its salts in enantiomeric form or as a racemate.

According to one aspect of the present invention, the compound of formula (I) - wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹³ , X, Y, n, m and Ar are as defined above - can be prepared by the reaction processes of Figure 1.

(1) Reaction route: The compound of formula (IIIa) - where all symbols are as defined above - is reacted with the compound of formula (IIIb) - where Y is as defined above except for the group of formula NH, R ¹¹ is a straight or branched C 1-6 alkyl group and all other symbols are as defined above - to obtain the compound of formula (I) - where Y is as defined above except for the group of formula NH and all other symbols are as defined above. The reaction can be carried out in the presence of a base, which may be an alkali metal hydride such as NaH or KH; an organic lithium compound such as CH ₃ Li, BuLi, LDA (lithium diisopropyl *

amide), TMEDA and the like; alkoxide such as NaOMe, NaOEt, K ⁺ BuO and the like or mixtures thereof. The reaction can be carried out in the presence of a solvent such as diethyl ether, tetrahydrofuran (THF), dioxane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethylene glycol dimethyl ether (DME), toluene, benzene and the like or mixtures thereof. Hexamethylphosphoramide (HMPA) can be used as a cosolvent. The reaction can be carried out at a temperature between -78°C and 50°C, preferably between -10°C and 30°C. The reaction is more effective under anhydrous conditions. The compound of formula (IIIb) can be prepared by the Arbuzov reaction [Annal Chemie, 53:699 (1996)].

Alternatively, the compound of formula (I) can be prepared by reacting the compound of formula (IIIa), wherein all symbols are as defined above, with a Wittig reagent such as HarPh ₃ P ⁺ CH-(OR ³ )CO ₂ R ⁴ under similar conditions; R ³ and R ⁴ are as defined above.

(2) Reaction route: A compound of the general formula (Ilid) - where R ⁶ is as defined above, NR ⁸ R ⁹ , Y is as defined above except for the group of the formula NH and all other symbols are as defined above - is reacted with a compound of the general formula (lile) - where R ³ is as defined above except for the hydrogen atom and L ¹ is a leaving group such as a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like - to obtain a compound of the general formula (I). The reaction can be carried out in the presence of a solvent such as diethyl ether, THF, DMF, DMSO, DME, toluene, benzene and the like. The inert gas space may be nitrogen, argon, helium gas and the like. The reaction can be carried out in the presence of a base, such as KOH, NaOH, NaOMe, t-BuO'K ⁺ , NaH, KH, LDA, NaHMDS, (sodium hexamethyldisilazane), K ₂ CO ₃ , Na ₂ CO ₃ and the like. A phase transfer catalyst such as tetraalkylammonium halides, hydroxides or bisulfates can be used. The reaction can be carried out at a temperature of -20°C to 200°C, preferably 0°C to 150°C, for a reaction time of 1 to 72 hours, preferably 1 to 12 hours. Alkylating agents such as dialkylsulfates such as diethylsulfate or dimethylsulfate; alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like can also be used for the reaction.

(3) Reaction route: The compound of the general formula (IIIa) - where all symbols are as defined above - is reacted with the compound of the general formula (IIIa) - where R ² is a hydrogen atom, Y is as defined above, except for the group of the formula NH, and all other symbols are as defined above - in the presence of a base. The nature of the base is not critical, bases commonly used in aldol condensation can be used, for example, alkali metal hydrides such as NaH, KH, metal alkoxides such as NaOMe, t-BuOK ⁺ , NaOEt, metal amides such as LiNH ₂ , LiN(iPr) ₂ . An aprotic solvent can be used as a solvent, for example, THF, diethyl ether, dioxane. The reaction can be carried out in an inert gas atmosphere, for example, nitrogen, argon, helium gas. The reaction proceeds more efficiently under anhydrous conditions. The reaction can be carried out at temperatures between -80°C and 35°C. The initially formed β-hydroxy product can be dehydrated under conventional conditions, for example using p-TSA in a solvent such as benzene or toluene. The choice of solvent and dehydrating agent is not critical. The reaction can be carried out at temperatures between 20°C and the boiling point of the solvent, preferably by refluxing the reaction mixture and continuously removing water using a Dean Stark water trap.

(4) Reaction route: a compound of the general formula (IIIg) - wherein R ⁶ , R ¹³ , X and n are as defined above, L ¹ is a leaving group, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom; a ρ-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate group and the like, preferably a chlorine atom - is reacted with a compound of the general formula (IIIf) - wherein R ¹ and R ² together form a bond and all other symbols are as defined above - to obtain a compound of the general formula (I) as defined above. The reaction can be carried out in an aprotic solvent such as diethyl ether, THF, DMF, DMSO, DME, toluene, benzene, acetone, acetonitrile and the like or a mixture thereof. Nitrogen, argon, helium gas and the like can be used as an inert gas space. The reaction can be carried out in the presence of bases, such as K ₂ CO ₃ , Na ₂ CO ₃ , NaH or a mixture thereof. The reaction can be carried out at a temperature of -20°C to 120°C, preferably 0°C to 120°C; the reaction time is 1-48 hours. A tetraalkylammonium halide, hydroxide or bisulfate can be used as a phase transfer catalyst.

(5) Reaction route: The compound of formula (IIIlh) wherein R ⁶ , R ¹³ , X and the present are as defined above is reacted with the compound of formula (IIIlf) wherein R ¹ and R ² together form a bond, R ⁵ is a hydrogen atom, and all other symbols are as defined above using a suitable coupling agent, such as isobutyl chloroformate or ethyl chloroformate/Et ₃ N, pivaloyl chloride/Et ₃ N, dicyclohexyl urea, triaryl phosphine/dialkyl aza dicarboxylate such as PPh ₃ /DEAD, and the like. The reaction can be carried out in the presence of a solvent such as THF, DME, CH ₂ Cl ₂ , CHCl ₃ , toluene, acetonitrile, carbon tetrachloride, and the like. The inert gas space may be nitrogen, argon, helium, and the like. The reaction can be carried out in the presence of DMAP, 1-hydroxybenzotriazole (HOBt), of which 0.05-2, preferably 1.25-1 equivalent weight can be used. The reaction temperature can be between 0°C and 100°C, preferably 20°C and 80°C. The reaction time is 0.5-48 hours, preferably 0.5-24 hours.

(6) Reaction route: The compound of formula (Illii) - where all symbols are as defined above - is reacted with a compound of formula (Illj) - where Y is an oxygen atom, R ³ =R ⁴ and their meanings are as defined above except for the hydrogen atom, to obtain the compound of formula (I) - where R ¹ and R ² together form a bond, Y is an oxygen atom. The reaction can be carried out with the reagents alone in the presence of a base, which can be an alkali metal hydride such as NaH, KH or an organic lithium compound such as CH ₃ Li, BuLi and the like or an alkoxide such as NaOMe, NaOEt, tert-BuO K ⁺ and the like or a mixture thereof. The reaction can be carried out in the presence of an aprotic solvent such as THF, dioxane, DMF, DMSO, DME and the like or a mixture thereof. HMPA can be a co-solvent. The reaction can be carried out at a temperature between -78°C and 100°C, preferably between -10°C and 50°C. The reaction time is 1-48 hours.

In another embodiment of the present invention, the compound of formula (I) - wherein R ¹ is hydroxyl, alkoxy, halogen, lower alkyl, substituted or unsubstituted arylalkyl group; R ² is hydrogen, halogen, lower alkyl, alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl group, R , R , R , R , ^R , R , X, Y ^, Ar, m and n are as defined above - can be prepared via the reaction processes shown in Figure 2.

(7) Reaction route: The compound of formula (IVa), which corresponds to the compound of formula (I), wherein R ¹ and R ² together form a bond, Y is an oxygen atom and all other symbols are as defined above, and which can be prepared as described above (Figure 1), is reduced to the compound of formula (I), wherein R ¹ and R ² are hydrogen atoms and all other symbols are as defined above. The reaction can be carried out with hydrogen gas in the presence of a catalyst such as Pd/C, Rh/C, Pt/C and the like. A mixture of catalysts can also be used. The reaction can be carried out in the presence of a solvent such as dioxane, acetic acid, ethyl acetate, alcohol such as methanol, ethanol and the like. The pressure used is 275-550 kPa (40-80 psi). The catalyst may preferably be 5-10% Pd/C, and the amount used may be 5-100% (w/w). A metal in a solvent may also be used for the reaction, for example magnesium or samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation may be carried out with metal catalysts containing chiral ligands, to obtain the compound of general formula (I) in an optically active form. The metal catalyst may consist of rhodium, ruthenium, indium and the like. The chiral ligand may be a chiral phosphine, for example an optically pure enantiomer of 2,3-bis(diphenylphosphino)butane, 2,3-isopropylidene-2,3-dihydro-1,4-bis(diphenylphosphino)butane and the like. Any chiral catalyst can be used which yields the desired optically pure product of general formula (I) [Principles of Asymmetric Synthesis, Tetrahedron Series, vol. 14, pp. 311-316, ed. Baldwin J. E].

(8) Reactions: A compound of formula (IVb) - wherein R ⁶ is as defined above; R ⁴ is as defined above except for hydrogen, all other symbols are as defined above, L ¹ is a leaving group, for example, a halogen atom ^such as chlorine, bromine or iodine; methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate - is reacted with an alcohol to give a compound of formula (I). The reaction can be carried out in the presence of a solvent, which may be diethyl ether, THF, DMF, DMSO, DME, toluene, benzene and the like or a mixture thereof. The reaction can be carried out in an inert gas atmosphere, for example nitrogen, argon, helium gas, in the presence of a base, which can be KOH, NaOH, NaOMe, NaOEt, t-BuO K ⁺ , NaH, KH or a mixture thereof. A phase transfer catalyst can be used, such as tetraalkylammonium halides, bisulfates or hydroxides. The reaction can be carried out at a temperature between -20°C and 120°C, preferably between 0°C and 100°, and the reaction time is 1-48 hours, preferably 1-24 hours.

(9) Reaction route: The compound of the general formula (IIlg) defined above is reacted with a compound of the general formula (IIIf) - wherein each symbol is as defined above - to obtain the compound of the general formula (I) defined above. The reaction can be carried out in a solvent such as diethyl ether, THF, DMF, DMSO, DME, toluene, benzene, acetone, acetonitrile and the like or a mixture thereof. The reaction can be carried out in an inert gas space such as nitrogen, argon, helium gas. The reaction can be carried out in the presence of a base such as K ₂ CO ₃ , Na ₂ CO ₃ , NaH and the like or a mixture thereof. The reaction can be carried out at a temperature of -20°C to 120°C, preferably 1-120°C. The reaction time is 1-48 hours, preferably 1-24 hours. The phase transfer catalyst used can be a tetraalkylammonium halide or hydroxide.

(10) Reaction route: The compound of formula (IIIlh) as defined above is reacted with a compound of formula (IIIf) - where all symbols are as defined above - using a suitable coupling agent, such as isobutyl chloroformate, ethyl chloroformate/Et ₃ N or pivaloyl chloride/Et ₃ N, dicyclohexyl urea, triaryl phosphine/dialkyl aza dicarboxylate, such as PPh ₃ /DEAD and the like. The reaction can be carried out in the presence of a solvent, such as THF, DME, CH ₂ CI ₂ , CHCI ₃ , toluene, acetonitrile, carbon tetrachloride and the like. Nitrogen, argon, helium gas and the like can be used as the inert gas space. The reaction can be carried out in the presence of DMAP, HOBt, which can be used in an amount of 0.05-2, preferably 0.25-1 equivalent weight. The reaction temperature is 0-100°C, preferably 20-80°C. The reaction time is 0.5-48 hours, preferably 6-24 hours.

(11) Reaction route: The compound of the general formula (Ilid), which is the same as the compound of the general formula (I), wherein all symbols are as defined above, is reacted with a compound of the general formula (lile) - wherein R ³ is as defined above except for a hydrogen atom, L ¹ is a leaving group, for example, a halogen atom such as a chlorine, bromine or iodine atom, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate group and the like. The reaction may be carried out in the presence of a solvent such as diethyl ether, THF, DMF, DMSO, DME, toluene, benzene, acetone, acetonitrile and the like. The inert gas space may be nitrogen, argon, helium gas and the like. The reaction may be carried out in the presence of a base such as KOH, NaOH, NaOMe, t-BuOK ⁺ , NaH, KH, LDA, NaHMDS, K ₂ CO ₃ , Na ₂ CO ₃ and the like. A phase transfer catalyst such as tetraalkylammonium halides, hydroxides or bisulphates may be used. The reaction may be carried out at a temperature of -20°C to 200°C, preferably 0°C to 150°C. The reaction time is 1 to 72 hours, preferably 1 to 12 hours. An alkylating agent such as dialkyl sulphates such as diethyl sulphate or dimethyl

-sulfate, alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like.

(12) Reaction route: The compound of the general formula (IIIa) defined above is reacted with a compound of the general formula (IIIa) - wherein R ² is a hydrogen atom, Y is as defined above, except for the group of the formula NH and all other symbols are as defined above - under usual conditions. Any base commonly used for aldol condensation can be used, for example, metal hydrides such as NaH or KH; metal alkoxides such as NaOMe, tert-BuO'K ⁺ or NaOEt; metal amides such as LiNH ₂ , LiN(iPr) ₂ . An aprotic solvent such as THF, DMF or diethyl ether can be used. For example, argon gas can be used as an inert gas space, and the reaction can be carried out more efficiently under anhydrous conditions. The reaction can be carried out at a temperature of -80°C to 25°C. The β-hydroxy aldol product can be dehydroxylated by conventional methods, preferably by ionic hydrogenation techniques, such as reaction with a trialkylsilane in the presence of an acid such as trifluoroacetic acid. A solvent such as dichloromethane (CH ₂ Cl ₂ ) can be used. The dehydroxylation can also be carried out by the method of Barton [Barton DHR et al., J. Chern. Soc. Perkin Trans I, 1574 (1975); Martin FS et al., Tetrahedron Lett., 33: 1839 (1992)].

(13) Reaction route: The compound of the general formula (Vld) - where all symbols are as defined above - is converted into a compound of the general formula (I) in the presence of a base or an acid, where Y represents an oxygen atom and all other symbols are as defined above. The choice of base or acid is not critical. Any base that is commonly used for the hydrolysis of a nitrile into an acid can be used, such as metal hydroxides such as aqueous solutions of NaOH or KOH. Acids commonly used in the said reaction can also be used, for example, an alcohol such as methanol, ethanol, propanol, etc. in excess hydrogen chloride. The reaction can be carried out at a temperature between 0°C and the boiling point of the solvent, preferably between 25°C and the boiling point. The reaction time is 0.25 to 48 hours.

(14) Reaction route: The compound of formula (IVe) - where R ⁴ is as defined above except for hydrogen and all other symbols are as defined above - is reacted with the compound of formula (IVc) - where R ³ is as defined above except for hydrogen - to give the compound of formula (I). The reaction can be carried out in the presence of rhodium(II) salts, such as rhodium(II) acetate (the reaction is a rhodium-carbenoid-mediated incorporation reaction). The reaction can be carried out in the presence of a solvent, which can be benzene, toluene, dioxane, diethyl ether, THF and the like, or a combination thereof; or preferably a compound of formula R ³ OH can be used as the solvent at any suitable temperature at which the desired product is sufficiently formed; this can generally be done at an elevated temperature, for example at the boiling point of the solvent. Nitrogen, argon, helium gas can be used as the inert gas space. The reaction time is 0.4-24 hours, preferably 0.5-6 hours.

(15) Reaction route: The compound of formula (IVg) is reacted with a compound of formula (IVf) - wherein G ¹ and G ² are independently NH ₂ or CHO, q is an integer of 0-6, and all other symbols are as defined above - to obtain the compound of formula (I) - wherein R ⁵ is hydrogen, and all other symbols are as defined above. The reaction consists of two steps, first an imine is formed, and then this is reduced in the second step. The imine formation can be carried out in a solvent, which can be MeOH, EtOH, iPrOH and the like. The reaction can be carried out in the presence of a base, which can be sodium acetate, potassium acetate and the like or a mixture thereof. The reaction temperature can be between room temperature and the boiling point of the solvent. The reaction time is 2-24 hours, preferably 2-12 hours.

The imine can be obtained by reacting the compound of formula (IVg) with a compound of formula (IVf) - where G ¹ and G ² are independently NH ₂ or CHO, q is an integer of 0-6, and all other symbols are as defined above in a solvent, which can be CH ₂ Cl ₂ , chloroform (CHC ₃ ), chlorobenzene, benzene, THF, in the presence of a catalyst, which can be p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF ₃ -OEt ₂ and the like. The reaction can also be carried out in the presence of activated molecular sieves. The reaction can be carried out at a temperature of 10-100°C, preferably 10-60°C. The reaction time is 1-48 hours.

The imine obtained as above can be reduced with reducing agents such as Na(CN)BH ₃ -HCl [Hutchins, RO et al., J. Org. Chem., 48:3433 (1983)], NaBH ₄ , H ₂ .-Pd/C, H ₂ -Pt/C, H ₂ -Rh/C, etc. in solvents such as methanol, ethanol and the like.

The compound of formula (I) wherein R ⁵ is hydrogen can also be prepared in a single step reaction using compounds of formula (IVg) and (IVf) wherein all symbols are as defined above by reductive amination using hydrogen as the reducing agent. Compounds of formula (IVg) and (IVf) are condensed in hydrogen gas to give compound of formula (I). The pressure of hydrogen gas can vary in the range of 10-90 psi, preferably 20-60 psi. The solvent can be selected from MeOH, EtOH, dioxane, toluene and the like. The reaction can be carried out at a temperature between room temperature and 50°C, preferably room temperature and 40°C. The catalyst used can be Pd/C, Rh/C, Pt/C and the like.

The compound of formula (I) wherein R ⁴ is hydrogen can be prepared by hydrolysis of the compound of formula (I) wherein R ⁴ is as defined above except for hydrogen by conventional methods. The hydrolysis can be carried out in the presence of a base such as Na ₂ CO ₃ , K ₂ CO ₃ , NaOH, KOH, LiOH and the like and in a suitable solvent such as methanol, ethanol, water and the like or a mixture thereof. The reaction can be carried out at a temperature of 20-120°C. The reaction time is 2-48 hours, preferably 2-12 hours.

t

The compound of formula (I) wherein Y is oxygen and ^R4 is hydrogen or lower alkyl can be converted to a compound of formula (I) wherein Y is ^NR7 by reacting it with a suitable amine of formula ^NHR4R7 wherein ^R4 and ^R7 are as defined above. Alternatively, the compound of formula (I) wherein ^YR4 is hydroxyl can be converted to an acid halide, preferably ^an acid chloride ( ^YR4 =Cl), using a suitable reagent for the reaction, such as oxalyl chloride, thionyl chloride and the like, and then the halide is reacted with an amine of formula ^NHR4R7 wherein ^R4 and ^R7 are ^as defined above. Another method is to prepare a mixed anhydride of the compound of formula (I) wherein YR ⁴ is a hydroxyl group and all other symbols are as defined above by reacting it with an acid halide such as acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride and the like. The reaction can be carried out in the presence of pyridine, triethylamine, diisopropylethylamine and the like. A coupling reagent such as DCC/DMAP, DCC/HOBt, EDCI/HOBT, ethyl chloroformate, isobutyl chloroformate reagents can also be used to activate the acid. Halogenated hydrocarbons such as chloroform or dichloromethane; hydrocarbons such as benzene, toluene, xylene and the like can be used as solvents. The reaction can be carried out at a temperature of -40°C to 40°C, preferably 0°C to 20°C. The acid halides, mixed anhydrides or activated acids obtained with coupling agents thus prepared are further converted by reaction with amines of the general formula NR ⁴ R ⁷ , where R ⁴ and R ⁷ are as defined above, to give compounds of the general formula (I) wherein Y is a group of the general formula NR ⁷ and all other symbols are as defined above.

The invention further relates to the intermediate of general formula (IIIa), its derivatives, analogues, tautomeric forms, stereoisomers, salts, solvates, wherein in the general formula

R ⁵ represents a hydrogen atom, an alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl group, each of which groups may be substituted or unsubstituted; n and m represent an integer of 0-6; Ar represents a substituted or unsubstituted divalent group, phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl group and the like; X represents a group of the formula C=O, C=S, -C(0)CH ₂ -, -CH=CH-CH ₂ , -CH=CH-C0- or X represents a bond;

R is a group of the general formula -OSO 2 R 8 , OCONR 8 R 9 , -NR 8 COOR 9 , -NR 8 COR 9 , -NR 8 SO2R 9 , nr 8 conr 9 r 10 , -NR ₈ ^{CSNR 8} R ⁹ , -SO2R ⁸ , -SOR ⁸ , -SR ⁸ , -SO2NR ^{8 R 9} , ^{-SO2OR 8 ,} -COOR ⁹ , -COR ^{9 or -CONR 8 R 9 , each of which may be substituted} or unsubstituted, and R ⁸ , R ⁹ and R ¹⁰ are independently hydrogen, alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl, each of which may be substituted or unsubstituted; where R ⁸ and R ⁹ are on a nitrogen atom, they may together form a 5- or 6-membered ring structure consisting of carbon atoms and one or more heteroatoms which may be oxygen, sulfur or nitrogen atoms; or R ⁶ is hydrogen when R ³ is at the 3-position of the phenyl ring and is not hydrogen;

R ¹³ is hydrogen, halogen, nitro, cyano, amino, halogenated alkyl, hydroxyl or the following substituted or unsubstituted group: straight or branched, C1-C12 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxy40

ű. s? ·

-carbonyl-, aryloxy-, aryloxy-, alkylcarbonyloxy-, alkoxycarbonylamino-, aryloxycarbonylamino-, aryloxycarbonylamino-, fluorenylmethoxycarbonyl- (Fmoc), fluorenylmethoxycarbonylamino- (N-Fmoc),

a group of the general formula -oso ₂ r ⁸ , -OCONR ⁸ R ⁹ , NR ⁸ COOR ⁹ , -NR ⁸ COR ⁹ , -NR ⁸ R ⁹ , -NR ⁸ SO2R ⁹ , -nr ⁸ conr ⁹ r ¹⁰ , -nr ⁸ csnr ⁸ r ⁹ , -so2r ⁸ , -sor ⁸ , -sr ⁸ , -so2nr ⁸ r ⁹ , -so2or ⁸ , -COOR ⁹ , -COR ⁹ , -CONR ⁸ R ⁹ , where R ⁸ , R ⁹ and R ¹⁰ independently represent a hydrogen atom or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; when R ⁸ and R ⁹ are on a nitrogen atom, they can together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms.

The substituents of Ar, R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ and R ¹³ are the same as those listed in the description of general formula (I);

m and n are integers from 0 to 6.

Another embodiment of the invention is the preparation of a compound of formula (IIIa) - wherein R ⁵ is a hydrogen atom; X is a group of the formula -C(O)CH ₂ -, -CH=CH-CH ₂ - or X is a bond; m is 0; Ar is a phenyl group, and all other symbols are as defined above -, as illustrated by the reaction process in Figure 3.

The compound of formula (Ilik) - where all symbols are as defined above - is reacted with a compound of formula (III·) - where R ¹² is hydrogen or an alkyl group having 1-6 carbon atoms - to give the compound of formula (Ilim) - where all symbols are as defined above. The reaction consists of two steps, the first step forming the imine is followed by reduction. The imine formation can be carried out in a solvent such as methanol (MeOH), ethanol (EtOH), isopropanol (i-PrOH) and the like. The reaction can be facilitated by the presence of sodium acetate, potassium acetate and the like. · ·· · · .u. t. The reaction can be carried out at a temperature between room temperature and the boiling point of the solvent. The reaction time is 2-24 hours, preferably 2-12 hours.

The imine can also be obtained by reacting the compound of general formula (IIk) with the compound of general formula (IIk) in a solvent such as dichloromethane, chloroform, chlorobenzene, benzene, tetrahydrofuran (THF) in the presence of a catalyst such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, boron trifluoride diethyl etherate (BF ₃ -OEt ₂ ) and the like. The reaction can also be carried out in the presence of activated molecular sieves. The reaction is carried out at a temperature of 10-100°C, preferably 10-60°C. The reaction time is 1-48 hours.

The imine thus obtained can be reduced with sodium cyanoborohydride-HCl [Hutchins RO et al., J. Org. Chem., 48:3433 (1983)], sodium borohydride, H ₂ -Pd/C, H ₂ -Pt/C, H ₂ -Rh/C and similar reducing agents in solvents such as methanol, ethanol and the like.

The compound of formula (IIIm) - where all symbols are as defined above - can be hydrolyzed in the presence of a base or an acid to give a compound of formula (IIIa). The choice of base or acid is not critical. The base can be, for example, a metal hydroxide such as an aqueous solution of NaOH or KOH, the acid can be an aqueous solution of hydrochloric acid or trifluoroacetic acid. Dichloromethane, THF, acetone, methanol, ethanol, propanol, water, etc. can be used as a solvent. The reaction can be carried out at a temperature between 0°C and the boiling point of the solvent. The reaction time is 0.25-48 hours.

In another embodiment of the present invention, the compound of formula (IIIa) wherein R ⁵ is hydrogen or alkyl, m is 0, and all other symbols are as defined above can be prepared by reacting the compound of formula (IIIg) wherein all symbols are as defined above with a compound of formula (IIIn) wherein R ¹² is hydrogen or alkyl, R ⁵ is as defined above, and m is an integer of 0-6.

·..··-’ χ * ' 42

The reaction of the compound of formula (IIIg) with the compound of formula (IIIn) can be carried out in the presence _of a solvent such as THF, DMF, DMSO, DME, toluene, benzene, acetone, acetonitrile and the like or mixtures thereof. The reaction can be carried out in an inert gas atmosphere such as nitrogen, argon, helium and the like. The reaction can be carried out in the presence of a base such as _K2CO3 , _Na2CO3 , NaH and _the like or mixtures thereof. The reaction can be carried out at a temperature of 20-120°C, preferably 30-80°C. The reaction time is 1-24 hours, preferably 1-12 hours.

The intermediate of general formula (IIIf) and its preparation process are the subject of patent application PCT/IB02/04274.

It is understood that in any of the above reactions any reactive group of the reagents is protected in accordance with standard chemical practice. Suitable protecting groups for the hydroxyl group and the phenolic hydroxyl group in any of the above reactions may be tert-butyldimethylsilyl, methoxymethyl, triphenylmethyl, benzyloxycarbonyl, THP, etc.; the amino and anilino groups may be protected with N-Boc, N-Cbz, N-Fmoc, benzophenoneimine, etc.; the aldehyde group may be protected as an acetal, the ketone group as a ketal. The application and removal of the protecting groups may be carried out by conventional methods appropriate to the molecule to be protected.

In the preparation of pharmaceutically acceptable salts, the compound of formula (I) is reacted with 1 to 4 equivalents of a base, such as sodium hydroxide, sodium methoxide, sodium hydride, potassium hydroxide, potassium tert-butoxide, calcium hydroxide, magnesium hydroxide and the like, in a solvent, such as diethyl ether, THF, methanol, tert-butanol, dioxane, isopropanol, ethanol, etc. A mixture of solvents may also be used. Organic bases, such as lysine, arginine, diethanolamine, choline, guaniditol, tromethamine and derivatives thereof, may also be used. Where possible, acid addition salts may also be prepared by reaction with acids. The acid may be, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, fumaric acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like. As a solvent, ethyl acetate, diethyl ether, alcohols, acetone, THF, dioxane, etc., or mixtures thereof, can be used.

The stereoisomers of the present invention may be prepared by using the reactants in the form of their individual enantiomers in the preparation processes, where possible; by carrying out the reaction in the presence of reagents or catalysts in their individual enantiomeric form; or by resolving the mixture of stereoisomers by conventional methods. A preferred method may be microbiological resolution, resolution of diastereomeric salts, which salts may be formed with chiral acids, such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like, or with chiral bases, such as brucine, cinchona alkaloids or derivatives thereof and the like. Commonly used methods are summarized in Jaques et al., Enantiomers, Racemates and Resolution (Wiley Interscience, 1981). In particular, the compound of formula (I), where YR ¹⁰ is a hydroxyl group, can be converted into a 1:1 mixture of diastereomeric amides by reaction with chiral amines, amino acids, amino alcohols derived from amino acids. The conversion to the amide can be carried out under conventional reaction conditions. The diastereomers can be separated by fractional crystallization or chromatography, and the stereoisomers of the compound of formula (I) can then be obtained by hydrolysis of the pure diastereomeric amide.

The various polymorphs of the compound of formula (I) which are part of the present invention can be obtained by crystallization of the compound of formula (I) under different conditions, for example, using different commonly used solvents or mixtures thereof, performing the crystallization at different temperatures, and cooling at different rates, from very rapid cooling to very slow cooling. Polymorphs can also be obtained by heating or melting the compounds and then gradually or rapidly cooling them.

'%. X. ·*> >> «’ ► » 44

Solid-state NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, X-ray powder diffraction, or other such techniques can be used to detect the presence of polymorphs.

The present invention also provides pharmaceutical compositions comprising the compound of formula (I), its derivative, analog, tautomeric form, stereoisomer, polymorph, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof as defined above, together with a pharmaceutically acceptable carrier, diluent and the like. These pharmaceutical compositions are useful for the treatment and/or prevention of hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular disease and disorders related thereto, and for the treatment of familial hypercholesterolemia, hypertriglyceridemia, and for the reduction of atherogenic lipoproteins, VLDL and LDL.

The compounds of the present invention are useful in the treatment of certain renal diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy. The compounds of formula (I) are also useful in the treatment and/or prevention of insulin resistance (type 11 diabetes), impaired glucose tolerance, leptin resistance, dyslipidemia, syndrome X-related disorders such as hypertension, obesity, insulin resistance, coronary artery disease and other cardiovascular diseases.

The compounds of the present invention can be used as aldose reductase inhibitors, to improve cognitive function in dementia, as anti-inflammatory agents, for the treatment of diabetic complications, diseases associated with endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.

The compounds of the present invention can also be used in combination with one or more HMG CoA reductase inhibitors, cholesterol absorption inhibitors, anti-obesity agents, lipoprotein disorder treatment agents, hypoglycemic agents, insulin, biguanides, sulfonylureas, thiazolidinediones, dual PPAR-α and γ agonists, or mixtures thereof for the treatment and/or prevention of the above-mentioned diseases. The compounds of the present invention used in combination with the HMG CoA reductase inhibitor, cholesterol absorption inhibitor, anti-obesity agent, hypoglycemic agent can be administered at the same time as the aforementioned or within a period of time when their synergistic effect is still exerted.

The present invention also provides pharmaceutical compositions comprising a compound of formula (I), a derivative, an analog, a tautomeric form, a stereoisomer, a polymorph, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof as defined above, in combination with one or more HMG CoA reductase inhibitors, cholesterol absorption inhibitors, anti-obesity agents, agents for treating lipoprotein disorders, hypoglycemic agents, insulin, biguanides, sulfonylureas, thiazolidinediones, dual-acting PPAR-α and γ agonists, or mixtures thereof, accompanied by a pharmaceutically acceptable carrier, diluent, and the like.

Pharmaceutical preparations may be formulated in conventional manner, i.e., they may be in the form of tablets, capsules, powders, syrups, solutions, suspensions, and the like, which may contain flavorings, sweeteners, solid or liquid carriers or diluents, or they may be in the form of injectable solutions or suspensions in sterile media. These preparations generally contain 1 to 20% by weight, preferably 1 to 10% by weight, of the active ingredient, the remainder of the preparation being carriers, diluents, solvents.

The pharmaceutically acceptable carrier may be a solid filler or diluent and a sterile aqueous or organic solution. The compositions contain the active ingredient in an amount that permits the dosage as described above.

For oral administration, the compounds may be formulated with a suitable solid or liquid carrier or diluent into tablets, powders, syrups, solutions, suspensions and the like. If necessary, the pharmaceutical compositions may contain additional additives such as flavorings, sweeteners, binders and the like. For parenteral administration, the compounds are used in the form of injectable solutions or suspensions in sterile aqueous or organic media. This may be, for example, a solution in sesame or peanut oil, aqueous propylene glycol and the like, an aqueous solution of a pharmaceutically acceptable water-soluble acid or base addition salt. An aqueous solution of the active ingredient in polyhydroxylated castor oil may also be used as an injectable solution. The injectable solutions thus prepared may be administered intravenously, intraperitoneally, subcutaneously or, preferably, intramuscularly.

For nasal administration, the compounds of the present invention may be dissolved or suspended in a liquid medium, particularly an aqueous medium, which preparation may be used as an aerosol. The medium may contain additives such as solubilizers such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.

Tablets, dragees or capsules containing talc and/or a hydrocarbon binder are particularly suitable for any oral administration. Preferred carriers for capsules, dragees and tablets are lactose, corn starch and/or potato starch. Syrups or elixirs may be used, where a sweetened carrier may be used.

The compounds of formula (I) as defined above can be used clinically in mammals, including humans, by oral or parenteral routes. Oral administration is preferred because it is more convenient and avoids the pain and irritation associated with injection. However, in cases where the patient is unable to swallow the drug, or when absorption after oral administration is insufficient due to disease or other disorder, it is essential to administer the drug parenterally. For any route of administration, the daily dose is 0.01100 mg/kg, preferably 0.01-50 mg/kg, which can be administered in single or divided doses. However, the optimal dose for a given patient is determined on an individual basis, generally starting with lower doses and then increasing the dose to determine the most suitable dose to which the patient responds optimally.

The compounds of the present invention reduce abnormal blood sugar, triglyceride, total cholesterol, LDL and VLDL levels and increase HDL levels through an agonist mechanism. This has been demonstrated in vitro and in vivo in animal experiments.

A) In vitro studies

a) Determination of hPPARα activity

The ligand binding domain of hPPARα is fused to the DNA binding domain of the yeast GAL4 transcription factor in a eukaryotic expression vector. Using Superfect (Qiagen, Germany) transfection reagent, this plasmid and a reporter plasmid containing the luciferase gene driven by the GAL4 specific promoter are transfected into HEK-293 cells. 40 hours after transfection, test compounds are added to the cells at various concentrations and incubated overnight. Luciferase activity as a function of the PPARα compound binding/activation capacity is measured using a Packard Luclite kit (Packard, USA) on a Top Count instrument [Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis, Gene, 118: 137-141 (1992); Superfect Transfection Reagent Handbook, February 1997, Qiagen, Germany)].

b) Determination of hPPARγ activity

The ligand binding domain of hPPARγ is fused to the DNA binding domain of the transcription factor GAL4 in a eukaryotic expression vector. Using Lipofectamine (Gibco BRL, USA) transfection reagent, HEK-293 cells are transfected with this plasmid and a reporter plasmid containing a luciferase gene driven by a GAL4 specific promoter. 48 hours after transfection, the test compound is added to the cells at a concentration of 1 pmol/l and incubated overnight. Luciferase activity, as a function of the PPARγ compound binding/activation capacity, is measured using a Packard Luclite kit (Packard, USA) on a Top Count apparatus [Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis, Gene, 118: 137-141 (1992); Guide to Eukaryotic Transfections with Cationic Lipid Reagents, Life Technologies, GIBCO BRL, USA].

Table 1

compound number concentration PPARa concentration PPARy 42 50 pmol/l 9.4 1 pmol/l 0.7 43 50 pmol/l 6.1 1 pmol/l 0.7 55 50 pmol/l 8.5 1 pmol/l 0.8

c) Determination of inhibition of HMG CoA reductase activity

The reductase bound to liver microsomes is prepared from rats fed 2% cholestyramine during the middle of the dark period. Spectrophotometric studies are performed in a reaction mixture with the following composition: 100 mmol/l potassium dihydrogen phosphate, 0.2 mmol/l dithiothreitol (DTT), 0.2 mmol/l NADPH, 0.3 mmol/l HMG CoA and 125 pg liver microsomal enzyme. The total volume of the reaction mixture is 1 ml. The reaction is initiated by the addition of HMG CoA. The reaction mixture is kept at 37°C for 30 minutes and the decrease in light absorption is measured at a wavelength of 340 nm. The blank sample contains no substrate [Goldstein, J. L. and Brown M. S., Progress in understanding the LDL receptor and HMG CoA reductase, two membrane proteins that regulate the plasma cholesterol., J. Lipid Res.,25:1450-1461 (1984)]. The test compounds inhibit the activity of HMG CoA reductase.

B) In vivo studies

a) Efficiency tested in genetic models

By mutating laboratory animals and distinguishing between different responses to daily diet, animal models have been developed that exhibit non-insulin-dependent diabetes and obesity, as well as hyperlipidemia associated with insulin resistance. Several laboratories have developed such db/db and ob/ob mouse models and Zucker fa/fa rat models to study the pathophysiology of the diseases and to test new antidiabetic drugs [Diabetes, 31(1): 1-6 (1982); Diabetes, 32:830-838 (1983); Annu. Rep. Sankyo Res. Lab., 46:1-57 (1994)].

The C57 BL/KsJ-db/db homozygous mouse, created by the Jackson Laboratory (USA), is obese, hyperglycemic, hyperinsulinemic, and insulin resistant [J. Clin. Invest., 85:962-967 (1990)], while the heterozygous animal is lean and has normal blood sugar levels. In the db/db model, the mouse becomes increasingly insulinopenic with advancing age, when its blood sugar control is inadequate, and features of the late stage of human type 11 diabetes can be observed. The state and fate of the pancreas change according to the model. Since this model resembles diabetes mellitus, the blood sugar and triglyceride lowering activity of the compounds of the present invention can be studied in it.

For the experiments, we used 8-14-week-old male C57BL/KsJ-db/db mice, weighing 35-60 g, bred in the Dr. Redy's Research Foundation (DRF) animal house. The animals were allowed to consume standard chow (National Institute of Nutrition (NIN), Hyderabad, India) and acidified water ad libitum. In the studies, we used animals with blood glucose levels above 350 mg/dl. 4 animals per group.

The test compounds are suspended in 0.25% carboxymethylcellulose and administered orally via gavage at doses ranging from 0.1 to 30 mg/kg/day for 6 days. Control animals receive vehicle only (10 ml/kg). On day 6, blood samples are taken one hour after administration of the test compound or vehicle.

To measure blood glucose and triglyceride levels, a 100 μl blood sample is taken from the orbital sinus using a heparinized capillary for blood collection and centrifuged in a tube containing EDTA. The glucose and triglyceride concentrations in the resulting plasma are determined spectrophotometrically using the glucose oxidase and glycerol-3-PO ₃ -oxidase/peroxidase enzyme methods (Dr. Redy's Lab., Diagnostic Division Kits, Hyderabad, India).

The blood glucose and triglyceride lowering activity of the test compound was determined according to the formula.

Table 2

compound number dose (mg/kg) blood sugar level decrease (%) triglyceride level decrease (%) 44 3 15 39 67 3 56 36 70 3 63 56

b) Δ—plasma triglyceride and cholesterol lowering activity in a hypercholesterolemic rat model

Male Sprague Dawley rats (NIN) were bred in the DRF animal house. These animals were maintained at 25°C ± 1°C with a 12-hour light/12-hour dark cycle. Rats weighing 180-200 g were used for the experiments. Hypercholesterolemia was induced in animals fed 2% cholesterol and 1% sodium cholate mixed with their regular diet [National Institute of Nutrition (NIN), Hyderabad, India] for 6 days. The animals were maintained on the same diet throughout the experimental period [Petit, D., Bonnefis, M.T., Rey, C. and Infante, R., Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normo- and hyperlipidemic rats., Atherosclerosis, 74:215-225 (1988)].

Test compounds are administered orally at doses of 0.1-30 mg/kg/day for 3 days. Control animals receive vehicle only (10 ml/kg of 0.25% carboxymethylcellulose).

On days 1 and 3, blood samples were collected from the retroorbital sinus in a fasted state, one hour after treatment, using a heparinized capillary, and the samples were collected in EDTA-containing tubes. After centrifugation, the blood plasma was separated for determination of total cholesterol, HDL, and triglycerides. Triglycerides, total cholesterol, and HDL were measured using commercially available kits (Dr. Reddy's Laboratory, Diagnostic, Division, India). LDL and VLD cholesterol were calculated from total cholesterol, HDL, and triglycerides. The reduction in each parameter was calculated using the formula.

Table 3

compound number dose (mg/kg) decrease in total cholesterol (%) triglyceride level decrease (%) Increase in HDL level (%) LDL level reduction (%) 71 1 53 55 77 56

c) Investigation of plasma triglyceride and total cholesterol lowering activity in Swiss albino mice

Male Swiss albino mice (SAM) were obtained from the DRF animal house. The animals were maintained at 25°C ± 1°C with a 12-hour light/12-hour dark cycle. The animals were allowed to consume standard laboratory chow (NIN, Hyderabad, India) and water ad libitum. SAM mice weighing 20-25 g and guinea pigs weighing 500-700 g were used [Oliver, P., Plancke, M. 0., Marzin, D., Clavey, V., Sauzieres, J. and Fruchart, J. C., Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice. Atherosclerosis, 70:107-114 (1988)].

Swiss albino mice are given the test compound orally at doses ranging from 0.3 to 30 mg/kg/day for 6 days. Control animals receive vehicle only (10 ml/kg of 0.25% carboxymethylcellulose). Guinea pigs are given the test compound orally at doses ranging from 0.3 to 30 mg/kg/day for 6 days. Control animals receive vehicle only (10 ml/kg of 0.25% carboxymethylcellulose).

Blood samples were taken from the retroorbital sinus of the animals in the fasted state on days 0 and 6 after drug administration. The blood sample was collected with a heparinized capillary and centrifuged in EDTA-containing tubes. The plasma was aliquoted for determination of triglyceride and total cholesterol [Wieland, 0., Methods of Enzymatic analysis, edited by Bergermeyer, H. 0., pp. 211-214 (1963); Trinder, P. Ann. Clin. Biochem., 6:24-27 (1969)]. A commercial kit was used to measure triglyceride (Dr. Reddy's Diagnostic Division, Hyderabad, India).

Table 4

compound number dose (mg/kg) triglyceride reduction (%) 47 1 39 58 3 41 64 1 41 Results after 6 days

d) Study of the body weight-reducing effect in hamsters fed with cholesterol

Male Syrian hamsters were purchased from NIN (Hyderabad, India). Animals were housed in a DRF animal house with a 12-hour light/12-hour dark cycle at 25°C ± 1°C. Food and water were available ad libitum. From the day of treatment, animals were fed a standard diet (NIN) containing 1% cholesterol.

The animals are orally administered the test compound at a dose of 1-30 mg/kg/day for 15 days. Control animals are treated with vehicle only (10 ml/kg Mill Q water). The body weight of the animal is measured every 3 days.

Table 5

compound number dose (mg/kg) decrease in total cholesterol (%) triglyceride level decrease (%) weight loss (%) 44 3 63 77 19

φ · ·· · · .U. ί

The formulas used for the calculation are:

1) To calculate the concentration of blood sugar, triglycerides and total cholesterol, we use the following formula:

TT/OT percentage decrease (%) = [ 1--] x 100

TC/OC where

OC = day 0 value of the control group

OT = day 0 value of the treated group

TC = test day value of the control group

TT = test day value of the treated group

2) LDL and VLDL cholesterol levels are calculated using the following formula: triglyceride

LDL cholesterol, mg/dl = [total cholesterol - HDL cholesterol--] mg/dl

VLDL cholesterol, mg/dl = [total cholesterol-HDL cholesterol-LDL cholesterol] mg/dl.

To illustrate the above, examples are given below. The examples are for illustrative purposes and do not limit the scope of the invention. Examples 1-28 show the preparation of intermediates for the preparation, and examples 29 and later show the preparation of compounds of the invention.

Example 1 (3-Methanesulfonyloxypropyl)phenylmethanesulfonate (1) (i) Step: To a suspension of 22.1 g (2.5 equivalents, 583 mmol) of lithium aluminum hydride in 1.0 liter of anhydrous tetrahydrofuran, a solution of 21 g (1.0 equivalents, 116 mmol) of methyl [3-(4-hydroxyphenyl)propionate] in 50 ml of tetrahydrofuran was added dropwise at room temperature. The reaction mixture was refluxed for 4-5 hours. Excess ethyl acetate was added to the reaction mixture, followed by 23 ml of water, 23 ml of 15% aqueous sodium hydroxide solution and 70 ml of water with constant stirring at room temperature. The pH of the reaction mixture was adjusted to pH = 7.0 with hydrochloric acid. The reaction mixture was filtered through celite, the filtrate was washed with ethyl acetate. The combined filtrate was dried over sodium sulfate and evaporated. The residue was chromatographed (ethyl acetate/hexane) to give 17 g (100%) of 3-(4-hydroxyphenyl)propanol as a white solid. M.p.: 52-54°C.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.78-1.86 (m, 2H), 2.63 (t, 2H, J = 7.9 Hz), 3.67 (t, 2H, J = 6.3 Hz), 6.74 (d, 2H, J = 8.8 Hz), 7.05 (d, 2H, J = 8.8 Hz). IR (neat) cm' ¹ : 3485, 3029, 2940, 1505. TS m/z (Cl): 152 (M+1).

Step (ii): To a solution of 17 g (1.0 equivalent weight, 111.8 mmol) of 3-(4-hydroxyphenyl)propanol obtained in step (i) and 93.3 ml (6.0 equivalent weight, 670.8 mmol) of triethylamine in 550 ml of dichloromethane at 0°C was added dropwise 26 ml (3.0 equivalent weight, 335.4 mmol) of methanesulfonyl chloride. The reaction mixture was stirred at room temperature for 16 hours, then diluted with dichloromethane, the organic phase was washed with dilute hydrochloric acid, water and brine. The organic phase was dried over sodium sulfate and evaporated. The crude product was recrystallized from diisopropyl ether to give the desired product. The remaining mother liquor was evaporated and chromatographed (ethyl acetate/hexane) to give additional desired compound. A total of 20.8 g (61%) of desired product was obtained as a white solid. Mp.: 60-62°C. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 2.00-2.18 (m, 2H), 2.77 (t, 2H, J = 7.8 Hz), 3.00 (s, 3H), 3.13 (s, 3H), 4.23 (t, 2H, J = 6.3 Hz), 7.22 (aromatic, 4H). IR (neat) cm' ¹ : 3029, 2935, 1504. TS m/z (Cl): 309 (M+1).

Example 2

3-(3-Methanesulfonyloxypropyl)phenylmethanesulfonate (2)

The title compound was prepared according to the procedure described in Example 1.

Step (i): From methyl [3-hydroxyphenylpropionate], 3-(3-hydroxyphenyl)propanol is obtained in 100% yield as a liquid product.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.80-1.88 (m, 2H), 2.64 (t, 2H, J = 7.9 Hz), 3.49 (broad, -OH), 3.67 (t, 2H, J = 6.5 Hz), 6.65-6.76 (aromatic, 3H), 7.09-7.17 (aromatic, 1H). IR (neat) cm' ¹ : 3353, 2932, 2859, 1590. TS m/z (Cl): 152 (M+1).

Step (ii): 900 mg (1.0 equivalent weight, 5.92 mmol) of the 3-(3-hydroxyphenyl)propanol obtained in step (i) was used to obtain 3-(3-methanesulfonyloxy)phenyl)methanesulfonate as a white solid in 52% yield. M.p.: 60-62°C.

¹ H-NMR (CDCl3, 200 MHz), δ: 2.00-2.18 (m, 2H), 2.79 (t, 2H, = 7.8 Hz), 3.00 (s, 3H), 3.15 (s, 3H), 4.22 (t, 2H, J = 6.4 Hz), 7.10-7.20 (aromatic, 3H), 7.21-7.40 (m, 1H). IR (neat) cm' ¹ : 3030, 2941, 1586. TS m/z (Cl): 309 (M+1).

Example 3

4-(3-(Toluene-4-sulfonyloxy)propyl)phenyltoluene-4-sulfonate (3)

To a solution of 2.5 g (1.0 eq, 16.44 mmol) of 3-(4-hydroxyphenyl)propanol obtained in step (i) of Example 1 in 82 ml of dichloromethane and 11.4 ml (5.0 eq, 82.2 mmol) of triethylamine was added dropwise at 0°C to 9.4 g (3.0 eq, 49.3 mmol) of toluene-4-sulfonyl chloride. The reaction mixture was stirred at room temperature for 16 hours, then diluted with excess dichloromethane, the organic phase was washed with water and brine. The organic phase was dried over sodium sulfate and evaporated, and the resulting crude product was purified by chromatography (ethyl acetate/hexane) to give 5.1 g (66.7%) of the desired compound as a thick liquid. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.90 (quintet, 2H, J = 7.9 Hz), 2.44 (s, 6H), 2.61 (t, 2H, J = 6.8 Hz), 3.98 (t, 2H, J = 6.3 Hz), 6.83 (d, 2H, J = 8.8 Hz), 6.97 (d, 2H, J = 8.8 Hz), 7.32 (t, 2H, J = 7.5 Hz), 7.67 (d, 2H, J = 8.3 Hz), 7.76 (d, 2H, J = 8.3 Hz). IR (neat) cm' ¹ : 2926, 1597, 1502, 1364. TS m/z (Cl): 461 (M+1).

Example 4

2-(4-Nitrophenoxy)ethyl bromide (4)

A mixture of 1.0 g (1.0 equivalent weight, 7.19 mmol) of 4-nitrophenol, 3.85 ml (6.0 equivalent weight, 43.1 mmol) of 1,2-dibromoethane and 3.0 g (3 equivalent weight, 21.5 mmol) of waterZ. .s'. O »’ free potassium carbonate in 36 ml of anhydrous acetone was stirred at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was evaporated. The evaporation residue was redissolved in ethyl acetate and the solution was washed with aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, evaporated and the residue was chromatographed (ethyl acetate/hexane) to give 540 mg (32%) of the title compound as a solid. M.p.: 168°C.

¹ H-NMR (CDCI _3i 200 MHz), δ: 3.67 (t, 2H, J = 6.1 Hz), 4.38 (t, 2H, J = 6.1 Hz), 6.97 (d, 2H, J = 8.7 Hz), 8.20 (d, 2H, J = 8.7 Hz). IR (neat) cm' ¹ : 2925, 1592, 1511, 1330. TS m/z (Cl): 245 [M( ⁷⁹ Br)], 2.46 [M( ⁷⁹ Br)+ 1], 247 [M( ⁸¹ Br)], 248 [M( ⁸¹ Br)+ 1], Example 5

Ethyl-[2-ethoxy-3-(4-aminophenyl)propionaf| (5) (i) Step: 26.5 g (1.5 equivalents, 99.3 mmol) of triethyl-(2-ethoxyphosphonoacetate) and 5.3 g (2 equivalents, 132.4 mmol) of sodium hydride (50% suspension in oil) in 350 ml of tetrahydrofuran at 0°C were used to prepare the Wittig salt. 10 g (1 equivalent, 66.2 mmol) of solid 4-nitrobenzaldehyde were added portionwise at 0°C and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous ammonium chloride solution. The 11 g crude product is a mixture of (Z) and (E) stereoisomers of ethyl (p-nitro-2-ethoxycinnamate).

Step (ii): The ethyl (p-nitro-2-ethoxycinnamate) obtained in step (i) was hydrogenated in 150 ml of ethyl acetate in the presence of 10% palladium on carbon catalyst under 4.1 bar (60 psi) of hydrogen at room temperature. The reaction mixture was chromatographed (ethyl acetate/hexane) to give 9.41 g (60%) of the title compound as a thick oil. ¹ H-NMR (CDCl3, 200 MHz), δ: 1.16 (t, 3H, J = 7.0 Hz), 1.22 (t, 3H, J - 7.0 Hz), 2.90 (d, 2H, J = 6.3 Hz), 3.30 (broad s, 2H, NH2), 3.35 (m, 1H), 3.55 (m, 1H), 3.94 (t, 1H,J = 6.3 Hz), 4.15 (q, 2H, J = 7.0 Hz), 6.62 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.0 Hz). IR (neat) cm' ¹ : 3372, 1738. TS m/z (Cl): 238(M+1), 192 (M-OC 2 H ₅ ).

• ·· · * .»»-’·“ ·

Example 6

Methyl-r2-ethoxy-3-(4-aminophenyl)propionate1 (6) (i) Step: A Wittig salt was prepared from 34.3 ml (2 equivalents, 132 mmol) of triethyl-(2-ethoxyphosphonoacetate) and 6.28 g (2 equivalents, 132 mmol, 50% suspension in oil) of sodium hydride in 350 ml of tetrahydrofuran at 0°C. To this was added 10 g (1 equivalent, 66 mmol) of solid p-nitrobenzaldehyde in portions at 0°C. The resulting solution was stirred at room temperature for 16 hours, then diluted with ethyl acetate and washed with aqueous ammonium chloride solution. 15 g (86%) of crude product are obtained, which is a mixture of the (Z) and (E) stereoisomers of ethyl (p-nitro-2-ethoxycinnamate).

Step (ii): 15 g (1 equivalent, 56.6 mmol) of the crude product obtained in step (i) was dissolved in 250 ml of methanol and 35.6 g (10 equivalent, 566 mmol) of ammonium formate and 40 g of 10% palladium/carbon catalyst were added to the solution. The reaction mixture was allowed to stir at room temperature for 16 hours, then the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was diluted with ethyl acetate and washed with water and brine. The crude product was chromatographed to give 10 g (75%) of ethyl-(2-ethoxy-p-aminocinnamate) as a mixture of (E) and (Z) isomers.

Step (Hi): 10 g (1 equivalent, 42.5 mmol) of ethyl (2-ethoxy-p-aminocinnamate) obtained in step (ii) was reacted with 20.4 g (20 equivalents, 850 mmol) of magnesium in 500 ml of anhydrous methanol. The reaction mixture was refluxed for 2-3 hours and then stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and quenched with cold aqueous ammonium chloride. The organic phase was washed with water and brine. The residue was chromatographed (ethyl acetate/hexane) to give 8.06 g (80%) of the title compound as a thick oil. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.64 (t, 3H, J = 6.8 Hz), 2.90 (d, 2H, J = 6.3 Hz), 3.22-3.42 (m, 1H), 3.42-3.65 (m, 2H), 3.70 (s, 3H), 3.96 (t, 1H, J = 6.8 Hz), 6.61 (d, 2H, J = 8.3 Hz), 7.00 (d, 2H, J = 8.3 Hz). IR (neat) cm' ¹ : 3350 (broad), 1735.

-.··*·* · · ' - ¹ ·· '''**' *

TS m/z (Cl): 224 (M+1).

Example 7

Ethyl-r2-ethoxy-3-(3-aminophenyl)propionate1 (7)

The title compound was obtained from 3-nitrobenzaldehyde as described in Example 5 in 60% yield (two steps) as a viscous oil.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.17 (t, 3H,J = 7 Hz), 1.22 (t, 3H, J = 7 Hz), 2.91 (d, 2H,J = 6.7 Hz), 3.30-3.48 (m, 1H), 3.48-3.62 (m, 1H), 4.00 (t, 1H, J = 6.7 Hz), 4.17 (q, 2H, J = 7 Hz), 6.50-6.70 (aromatic, 3H), 7.06 (t, 1H, J = 7.5 Hz). IR (neat) cm' ¹ : 3374, 2978, 1738, 1606. TS m/z (Cl): 238 (M+1).

Example 8

Ethyl-r2-isopropoxy-3-(4-nitrophenyl)propionate1 (8) (i) Step: To a mixture of 50 ml of anhydrous ethanol and 5 ml of thionyl chloride at -5°C was added portionwise 5 g (1 equivalent weight) of 4-nitrophenylalanine. The reaction mixture was stirred at this temperature for 1 hour, then stirring was continued at room temperature for 16 hours. The reaction mixture was concentrated on a rotary evaporator, azeotroped with toluene, and dried under high vacuum to give 4-nitrophenylalanine ethyl ester hydrochloride in quantitative yield as a white solid.

Step (ii): 2 g (1.0 eq, 7.28 mmol) of 4-nitrophenylalanine ethyl ester hydrochloride obtained in step (i) was dissolved in 150 ml of ethyl acetate. To the solution was added 386 mg (0.5 eq, 3.64 mmol) of sodium carbonate and stirred for 15 minutes. The reaction mixture was washed with aqueous sodium bicarbonate, the organic phase was dried over sodium sulfate, and evaporated to give 1.55 g (89%) of 4-nitrophenylalanine ethyl ester as a viscous oil.

Step (Hi): 1.55 g (1.0 equivalent weight, 6.51 mmol) of 4-nitrophenylalanine ethyl ester obtained in step (ii) above was dissolved in 33 ml of chloroform. To the solution were added 20 µl (0.05 equivalent weight, 0.33 mmol) of glacial acetic acid and 958 µl (1.1 equivalent weight, 7.16 mmol) of isoamyl nitrite. The reaction mixture was refluxed for 30 minutes, then diluted with chloroform and washed with aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and carefully evaporated to give a yellowish liquid.

(arc) Step: 1.54 g (1.0 eq, 6.18 mmol) of the liquid obtained in step (iii) was dissolved in 31 ml of anhydrous isopropanol, and 38 mg (0.02 eq, 0.12 mmol) of rhodium tetraacetate 2-hydrate (Rh ₂ (OAc) 4.2H ₂ O) was added to the solution, and the reaction mixture was stirred at room temperature for 16 hours. The isopropanol was evaporated, and the reaction mixture was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and evaporated. The product was column chromatographed (ethyl acetate/hexane) to give 1.25 g (61% overall yield) of ethyl [2-isopropoxy-3-(4-nitrophenyl)propionate]. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 0.92 (d, 3H, J = 5.8 Hz), 1.16 (d, 3H, J = 5.8 Hz), 1.27 (t, 2H, J = 7.4 Hz), 3.00-3.10 (m, 2H), 3.52 (quintet, 1H), 4.08 (dd, 1H, J = 8.7 and 4.8 Hz), 4.21 (q, 2H, J = 7.4 Hz), 7.43 (d, 2H, J = 8.7 Hz), 8.16 (d, 2H, J = 8.7 Hz). IR (neat) cm' ¹ : 2975, 1747, 1602, 1522, 1347.

TS m/z (Cl): 282 (M+1).

Example 9

Ethyl-f2-isopropoxy-3-(4-aminophenyl)propionate1 (9)

1.52 g (5.4 mmol) of ethyl [2-isopropoxy-3-(4-nitrophenyl)propionate] obtained as described in Example 8 in 200 ml of ethyl acetate in the presence of 700 mg of 10% palladium/carbon catalyst was hydrogenated at 6.86 kPa at room temperature for 3-4 hours. The reaction mixture was filtered, the filtrate was evaporated under reduced pressure, and the residue was column chromatographed (ethyl acetate/hexane) to obtain 1.16 g (86%) of the desired ethyl [2-isopropoxy-3-(4-aminophenyl)propionate]. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 0.97 (d, 3H, J = 5.8 Hz), 1.15 (d, 3H, J = 5.8 Hz), 1.23 (t, 3H, J = 7.0 Hz), 2.80-2.95 (m, 2H), 3.49 (quintet, 1H), 3.98 (dd, 1H, J = 8.1 and 5.7 Hz), 4.16 (q, 2H, J = 7.0 Hz),

- .

6.61 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.3 Hz). IR (neat) cm' ¹ : 3455, 3371, 2975, 2929, 1737, 1626, 1519. TS m/z (Cl): 252 (M+1).

Example 10

4-Methanesulfonyloxybenzaldehyde (10)

In 200 ml of anhydrous dimethylformamide, 5.0 g (1.0 equivalent weight, 40.98 mmol) of 4-hydroxybenzaldehyde, 17 g (3 equivalent weight, 123 mmol) of anhydrous potassium carbonate and 4.76 ml (1.5 equivalent weight, 61.37 mmol) of methanesulfonyl chloride were stirred at room temperature for 16 hours. The reaction mixture was diluted with 200 ml of ethyl acetate, washed with water and brine. The organic phase was dried over sodium sulfate, evaporated and the resulting residue was chromatographed (ethyl acetate/hexane) to give 2.0 g (25%) of the title compound as a white solid. M.p.: 60-62°C.

¹ H-NMR (CDCl ₃ , 200 MHz), δ: 3.21 (s, 3H), 7.45 (d, 2H, J = 8.8 Hz), 7.95 (d, 2H, J = 8.8 Hz), 10.01 (s, 1H). IR (neat) cm' ¹ : 3024, 2932, 1701, 1591, 1502. TS m/z (Cl): 201 (M+1).

Example 11

2-(4-Hydroxyphenyl)-1-ethanol (11)

A solution of 3.0 g (18.07 mmol) of methyl-[2-(4-hydroxyphenyl)acetate] in 20 ml of tetrahydrofuran was added at 0°C to a stirred suspension of 0.86 g (23.49 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran. Stirring was continued at room temperature for 4 hours, the excess lithium aluminum hydride was quenched by adding saturated sodium sulfate solution, and the resulting precipitate was collected by filtration. The filtrate was extracted with ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was column chromatographed (50% ethyl acetate/petroleum ether) to give 1.1 g (44%) of the title compound as a white solid. Op.: 88-92°C. ¹ H-NMR (CDCI ₃ + DMSO-de, 200 MHz), δ: 2.75 (t, 2H,J = 7.1 Hz), 3.75 (t, 2H, J = 6.3 Hz), 6.75 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.3 Hz). TS m/z (Cl): 138 (M).

Example 12

4-(2-Methylsulfonyloxyethyl)phenylmethanesulfonate (12) 1.0 g (7.25 mmol) of 2-(4-hydroxyphenyl)-1-ethanol obtained as described in Example 11 in mL of dichloromethane was reacted with 2.52 mL (16.1 mmol) of triethylamine and 0.83 mL (15.9 mmol) of methanesulfonyl chloride at room temperature for 2 hours according to the procedure described in Step (ii) of Example 1. 2 g (94%) of the title compound were obtained. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 2.91 (s, 3H), 3.08 (t, 2H, J = 6.8 Hz), 3.15 (s, 3H), 4.42 (t, 2H, J = 6.8 Hz), 7.20-7.34 (m, 4H). TS m/z (Cl): 199 (M-OSO ₂ Me).

Example 13

Methyl-r2-(4-methylsulfonyloxyphenyl)acetate1 (13)

1.5 g (9.04 mmol) of methyl-[2-(4-hydroxyphenyl)acetate] in 20 ml of dichloromethane was reacted with 3.14 ml (22.59 mmol) of triethylamine and 0.84 ml (10.84 mmol) of methanesulfonyl chloride at room temperature for 2 hours according to the procedure described in step (ii) of Example 1. 1.7 g (77%) of the title compound were obtained. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 3.14 (s, 3H), 3.64 (s, 2H), 3.71 (s, 3H), 7.24 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.8 Hz). TS m/z (Cl): 244 (M).

Example 14

2-(4-Methanesulfonyloxyphenyl)acetic acid (14)

To a solution of 0.95 g (3.89 mmol) of methyl-[2-(4-methylsulfonyloxyphenyl)acetate] obtained as described in Example 13 in 10 ml of methanol was added 2.06 g (19.48 mmol) of sodium carbonate dissolved in 5 ml of water, and the reaction mixture was stirred at room temperature for 24 hours. The methanol was evaporated, the residue was taken up in water, and the impurity was washed with ethyl acetate. The pH of the aqueous phase was adjusted to about 2, at which point the title compound precipitated, yielding 0.55 g (61.4%) of the title compound as a white solid. M.p.: 158-162°C. ¹ H-NMR (DMSO-d _6,200 MHz), δ: 3.32 (s, 3H), 3.62 (s, 2H), 7.28 (d, 2H, J = 8.9 Hz), 7.37 (d, 2H, J = 8.6 Hz). TS m/z (Cl): 331 (M+1), 230 (M).

Example 15

Methyl 4-nitrocinnamate (15) g (15.54 mmol) of 4-nitrocinnamic acid in 50 ml of methanol was cooled to 10°C, 1 ml of concentrated sulfuric acid was slowly added to the solution, and the reaction mixture was refluxed for 30 minutes. The methanol was removed under reduced pressure, 150 ml of ethyl acetate was added to the residue, and the solution was washed with water, saturated sodium bicarbonate solution, water, and finally brine. The organic phase was dried over sodium sulfate and evaporated to give 3 g (93%) of the title compound as an off-white solid. M.p.: 158-160°C.

¹ H-NMR (CDCl ₃ , 200 MHz), δ: 3.84 (s, 3H), 6.56 (d, 1H,J = 15.9 Hz), 7.64-7.78 (m, 3H), 8.25 (d, 2H, J = 8.9 Hz). TS m/z (Cl): 208 (M+1), 194 (M-CH ₃ ).

Example 16

Methyl [3-(4-aminophenyl)propionate1 (16)

To a solution of 1.5 g (7.25 mmol) of methyl (4-nitrocyanamate) obtained as described in Example 15 in 25 ml of dioxane was added 0.6 g of 10% palladium/carbon catalyst and the reaction mixture was hydrogenated at room temperature at 413 kPa (60 psi) for 20 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (50% ethyl acetate/petroleum ether) to give 1.07 g (82.5%) of pure title compound as an off-white solid. M.p. 142-144°C. ¹ H-NMR (CDCl3, 200 MHz), δ: 2.57 (t, 2H, J = 7.5 Hz), 2.85 (t, 2H, J = 7.8 Hz), 3.66 (s, 3H), 6.64 (d, 2H, J = 8.3 Hz), 7.00 (d, 2H, J = 8.3 Hz). TS m/z (Cl): 180 (M+1).

Example 17

3-(4-Aminophenyl)-1-propanol (17)

A cold solution of 0.48 g (2.7 mmol) of methyl-[3-(4-aminophenyl)propionate] obtained as described in Example 16 in 10 ml of tetrahydrofuran was added dropwise to a suspension of 132 mg (3.49 mmol) of lithium aluminum hydride in 10 ml of tetrahydrofuran at 0°C, and the reaction mixture was stirred at room temperature overnight. The unreacted lithium aluminum hydride was quenched by adding a saturated solution of sodium sulfate, the mixture was filtered through celite, and the filtrate was washed thoroughly with ethyl acetate. The filtrate and washings were combined, the organic phase was dried over sodium sulfate and evaporated. The residue was purified to give 0.27 g (66.7%) of the title compound as a yellow solid.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.88-1.92 (m, 2H), 2.60 (t, 2H, J = 7.5 Hz), 3.66 (t, 2H, J = 6.3 Hz), 6.63 (d, 2H, J = 8.1 Hz), 6.99 (d, 2H, J = 8.1 Hz) Hz). TS m/z (Cl): 152 (M+1).

Example 18

3-(4-Amino-4-tert-butoxyphenyl)-1-propanol (18)

To a solution of 0.5 g (3.3 mmol) of 3-(4-aminophenyl)-1-propanol obtained as described in Example 17 in 15 ml of dichloromethane at 0°C was added 1.4 ml of triethylamine followed by 0.84 ml (3.64 mmol) of Boc anhydride and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with 50 ml of dichloromethane, the organic phase was washed with water and brine, dried over sodium sulfate and evaporated to dryness. The residue was subjected to column chromatography to give 0.4 g (48%) of the title compound as a colorless oil.

¹ H-NMR (CDCl3, 200 MHz), δ: 1.44-1.53 (m, 9H), 1.78-1.93 (m, 2H), 2.64 (t, 2H, j = 7.6 Hz), 3.64 (t, 2H, J = 6.6 Hz), 6.41 (broad, 1H, D2O exchangeable), 7.10 (d, 2H, J = 8.3 Hz), 7.25 (d, 2H, J = 8.3 Hz). TS m/z (Cl): 252 (M+1), 152 (M-Boc).

Example 19

3-(4-tert-Butoxy-4-methylsulfonamidophenyl)propyl methanesulfonate (19)

To a solution of 0.5 g (3.3 mmol) of 3-(4-amino-4-tert-butoxyphenyl)-1-propanol obtained as described in Example 18 in 10 ml of dichloromethane at 0°C was added 1.4 ml of triethylamine followed by 0.27 ml (3.5 mmol) of mesyl chloride. The reaction mixture was stirred at room temperature for 4 hours, then diluted with 50 ml of dichloromethane, the organic phase was washed with water and brine, dried over sodium sulfate and evaporated to dryness to give 0.61 g (94%) of the title compound.

¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.50 (s, 9H), 1.95-2.10 (m, 2H), 2.68 (t, 2H, J = 7.5 Hz), 2.97 (s, 3H), 3.13 (s, 1H), 3.66 (s, 2H), 4.19 (t, 2H, J = 6.3 Hz), 7.08 (d, 2H, J = 8.3 Hz), 7.27 (d, 2H, J = 8.3 Hz). TS m/z (Cl): 329 (M-SO ₂ Me).

Example 20

Methyl 4-hydroxycinnamate (20)

As described in Example 15, after 20 hours of reaction of 2 g (12.18 mmol) of 4-hydroxycinnamic acid in 25 ml of methanol and 0.8 ml of concentrated sulfuric acid, the title compound is obtained as a brownish solid. M.p.: 144-146°C. ¹ H-NMR (CDCl3, 200 MHz), δ: 3.80 (s, 3H), 5.69 (broad, D ₂ O exchangeable), 6.30 (d, 1H„ 15.8 Hz), 6.85 (d, 2H, J = 8.6 Hz), 7.43 (d, 2H, J = 8.6 Hz), 7.64 (d, 1H, J = 16.1 Hz).

TS m/z (Cl): 179 (M+1).

Example 21 (E)-3-(4-Hydroxyphenyl)-2-propen-1-ol (21)

A solution of 1.5 g (8.43 mmol) of methyl (-4-hydroxycinnamate) obtained as described in Example 20 in 15 ml of tetrahydrofuran was added dropwise to a suspension of 416 mg of lithium aluminum hydride in 10 ml of anhydrous tetrahydrofuran at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The excess lithium aluminum hydride was quenched by adding saturated sodium sulfate solution. The mixture was filtered through a pad of celite, the filtrate was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (20% ethyl acetate in petroleum ether) to give 0.4 g (31.6%) of the title compound as an off-white solid. M.p.: 116-118°C.

¹ H-NMR (CD3OD 200 MHz), δ: 4.17 (d, 2H, J = 5.9 Hz), 6.15 (td, 1H, J = 5.9 and 15.8 Hz), 6.50 (d, 1H, J = 5.9Hz), 6.71 (d, 2H, J = 8.3 Hz), 7.23 (d, 2H, J = 8.3 Hz). J = 8.6 Hz).

TS m/z (Cl): 151 (M+1).

Example 22

4-[(E)-3-Chloro-1-propenyl-phenylmethanesulfonate (22)

In a similar manner to Example 19, 0.36 g (2.4 mmol) of (E)-3-(4-hydroxyphenyl)-2-propen-1-ol obtained as described in Example 21 in 10 ml of dichloromethane was treated with 0.83 ml of triethylamine and 0.41 ml of methanesulfonyl chloride to give 0.47 g (64%) of the title compound.

¹ H-NMR (CDCl ₃ , 200 MHz), δ: 3.14 (s, 3H), 4.24 (d, 2H, J = 7.0 Hz), 6.21-6.4 (m, 1H), 6.65 (d, 1H, J = 15.8 Hz), 7.25 (d, 2H, J = 8.6 Hz), 7.43 (d, 2H, J = 8.8 Hz).

TS m/z (Cl): 247 (M+1).

Example 23 (E)-3-(4-I-ethylsulfonyloxyphenyl)-2-propenoic acid (23)

0.53 g (36%) of (E)-3-(4-Methylsulfonyloxyphenyl)-2-propenoic acid was prepared from 1.0 g (6.1 mmol) of (E)-4-hydroxycinnamic acid, 20 ml of DCM, 2.12 ml (15.25 mmol) of triethylamine and 0.57 ml (7.32 mmol) of methanesulfonyl chloride in a manner similar to that described in Example 19. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 3.20 (s, 3H), 6.51 (d, 1H, J = 15.8 Hz), 7.36 (d, 2H, J = 8.6 Hz), 7.64 (d, 2H, J = 8.3 Hz), 7.81 (d, 1H, J = 15.8 Hz). TS m/z (Cl): 243 (M+1).

Example 24 (E)-3-(4-Methylsulfonyloxyphenyl)-2-propenoic acid (24) From 1.0 g (6.02 mmol) of 3-(4-hydroxyphenyl)propanoic acid in 1 ml of dichloromethane, 2.1 ml of triethylamine and 0.56 ml (7.23 mmol) of methanesulfonyl chloride were used as described in Example 19 to prepare 1.02 g (69.4%) of the title compound.

¹ H-NMR (CDCl 3 , 200 MHz), δ: 2.74 (t, 2H, J= 7.4 Hz), 3.00-3.09 (m, 2H), 3.14 (s, 3H), 7.14-7.37 (m, 4H). TS m/z (Cl): 245 (M+1).

Example 25

Ethyl [(2S)-3-(4-aminophenyl)-2-ethoxypropanoate] (25A) and

Ethyl-[(2R)-3-(4-amino-phenyl)-2-ethoxypropanoate (25B) (i) Step Ethyl-[3-(4-dibenzylamino-phenyl)-2-ethoxypropanoate] (25ia)

To a cooled solution of 2.0 g (8.44 mmol) of ethyl [2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 5 in 30 ml of anhydrous dimethylformamide was added 2.68 g (25.3 mmol) of sodium carbonate and the mixture was stirred for 15 minutes. 2.0 ml (16.88 mmol) of benzyl bromide was added dropwise to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 ml of water and extracted with 3x50 ml of ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness to give 3.42 g (97%) of the title compound as a yellow oil which was used in the next reaction step without purification. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.06-1.32 (m, 6H), 2.89 (d, 2H, J = 6.4 Hz), 3.28-3.48 (m, 1H), 3.52-3.70 (m, 1H), 3.95 (t, 1H, J = 6.6 Hz), 4.12 (q, 2H, J = 7.0 Hz), 4.63 (s, 4H), 6.67 (d, 2H, J = 7.0 Hz), 7.03 (d, 2H, J = 8.3 Hz), 7.15-7.43 (m, 10H). TS m/z(CI): 418 (M+1).

(ii) Step: 3-(4-Dibenzylaminophenyl)-2-ethoxypropionic acid-(25iia)

To a solution of 0.5 g (1.2 mmol) of the compound obtained in step (i) in 10 ml of methanol in 2 ml of water was added 380 mg (3.6 mmol) of sodium carbonate and the reaction mixture was stirred at room temperature for 3 days. The methanol was removed and the reaction mixture was diluted with 10 ml of water. The aqueous phase was extracted with ethyl acetate to remove non-polar impurities. The aqueous phase was adjusted to pH = 4 with 2N hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate phases were washed with brine (3x10 ml), dried over sodium sulfate and evaporated to give 0.340 g (74%) of the title compound. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.17 (t, 3H, J = 7.1 Hz), 2.82-3.05 (m, 2H), 3.29-3.67 (m, 2H), 3.97-4.09 (m, 1H), 4.63 (s, 4H), 6.67 8d, 2H, J = 8.8 Hz), 7.03 (d, 2H, = 8.3 Hz), 7.13-7.42 (m, 10H). TS m/z (Cl): 390 (M+1).

(iii) Step: N1-[(1S)-1-phenylpropyl-(2S)-3-(4-dibenzylaminophenyl)-2-ethoxypropanamide (25iiia) and

N1-[(1 S)-1-phenylpropyl-(2R)-3-(4-dibenzylaminophenyl)-2-ethoxypropanamide (25iiib)

To a cooled solution of 1.0 g (2.57 mmol) of the compound obtained in step (ii) in dry dichloromethane was added 172 mg (1.286 mmol) of 5-hydroxybenzotriazole and 592 mg (3.08 mmol) of EDCI. The reaction mixture was stirred at 0°C for 30 min (until a clear solution was formed), then 0.37 g (2.69 mmol) of L-phenylglycinol was added to the solution and stirring was continued at room temperature for 16 h. The reaction mixture was diluted with 25 ml of dichloromethane, washed with 3x25 ml of water, dried over sodium sulfate and evaporated. The diastereomers were separated on a silica gel column using 10-45% ethyl acetate in petroleum ether as eluent. 420 mg (32%) of compound (25iiia) were obtained as a white solid. M.p.: 110-112°C. 380 mg (29%) of compound (25iiib) were obtained.

(25iiia) ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.18 (t, 3H, J = 7.1 Hz), 2.74-3.12 (m, 2H), 3.46-3.64 (m, 2H), 3.87 (d, 2H, J = 5.4 Hz), 3.98 (dd, 1H, J = 6.9 and 3.7 Hz), 4.64 (s, 4H), 4.93-5.05 (m, 1H), 6.64 (d, 2H, J = 8.4 Hz), 7.02 (d, 2H, J = 8.3 Hz), 7.12-7.46 (m, 15H). TS m/z (Cl): 509 (M+1).

(25iiib) ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.13 (t, 3H, J = 7.6 Hz), 2.80-3.16 (m, 2H), 3.39-3.68 (m, 4H), 3.96 (dd, 1H, J = 3.9 and 5.5 Hz), 4.64 (s, 4H), 4.85-5.00 (m, 1H), 6.67 (d, 2H, J = 6.8 Hz), 6.97 (d, 2H, J = 6.8 Hz), 7.06 (d, 2H, J = 8.3 Hz), 7.12-7.42 (m, 13H). TS m/z (Cl): 509 (M+1).

(arc) Step: (2S)-3-(4-Dibenzylaminophenyl)-2-ethoxypropanoic acid (25iva)

410 mg (0.8 mmol) of compound (25iiia) were dissolved in 6 ml of dioxane and 4 ml of 1 mol/l sulfuric acid solution were added to the solution. The reaction mixture was refluxed for 24 h. The dioxane was removed under reduced pressure and the residue was diluted with 10 ml of water. The aqueous phase was extracted with 3x25 ml of ethyl acetate, the combined organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified on silica gel using 40% ethyl acetate in petroleum ether as eluent. 180 mg (58%) of the title compound were obtained. [a] ²⁵ D = 1.8° (c = 0.5, MeOH). ¹ H-NMR (CDCl3, 200 MHz), δ: 1.16 (t, 3H, J = 7.6 Hz), 2.80-3.07 (m, 2H), 3.43-3.68 (m, 2H), 4.16 (dd, 1H, J = 7.3 and 4.4 Hz), 4.61 (s, 4H), 6.65 (d, 2H, J = 8.3 Hz), 7.04 (d, 2H, J = 8.8 Hz), 7.12-7.39 (m, 10H). TS m/z (Cl): 390 (M+1).

(2R)-3-(4-Dibenzylaminophenyl)-2-ethoxypropanoic acid (25ivb)

0.5 g (0.98 mmol) of compound (iiib) was refluxed with 5 ml of 1 mol/l sulfuric acid in dioxane for 24 h, and then the procedure was continued as described for the preparation of compound (25iva), yielding 152 mg (60%) of compound (25ivb).

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.18 (t, 3H, J = 7.0 Hz), 2.83-3.05 (m, 2H), 3.40-3.67 (m, 2H), 4.03 (dd, 1H, J = 7.3 and 4.3 Hz), 4.63 (s, 4H), 6.67 (d, 2H,J = 8.6 Hz), 7.03 (d, 2H, J = 8.6 Hz), 7.15-7.40 (m, 10H). TS m/z (Cl): 390 (M+1).

(v) Step: Ethyl-[(2S)-4-(4-dibenzylaminophenyl)-2-ethoxypropanoate] (25va)

To a cooled solution of 1.2 g (3.08 mmol) of compound (25iva) in 30 ml of anhydrous dimethylformamide was added 1.277 g (9.25 mmol) of potassium carbonate and the reaction mixture was stirred at low temperature for 15 min. 0.75 ml (9.25 mmol) of ethyl iodide was added to the reaction mixture and stirring was continued at room temperature for 3 h. Water was added to the reaction mixture and extracted with ethyl acetate (3 x 30 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 1.1 g (85%) of the title compound.

¹ H-NMR (CDCl3, 200 MHz), δ: 1.09-1.30 (m, 6H), 2.90 (d, 2H, J = 6.5 Hz), 3.27-3.67 (m, 2H), 3.96 (t, 1H, J = 6.7 Hz), 4.14 (q, 2H, J = 7.3 Hz), 4.63 (s, 4H), 6.65 (d, 2H, J = 8.6 Hz), 7.03 (d, 2H, J = 8.3 Hz), 7.15-7.42 (m, 10H). TS m/z (Cl): 418 (M+1).

Ethyl-[(2R)-3-(4-Dibenzylaminophenyl)-2-ethoxypropanoate (25vb) .··. 'I '''J .«λ ·''· ·.·'* ^:

Following the procedure described for the preparation of (25va), 120 mg (74%) of compound (25vb) was obtained from 150 mg (0.39 mmol) of compound (25ivb), 156 mg (1.17 mmol) of potassium carbonate, and 0.09 ml (1.17 mmol) of ethyl iodide in anhydrous dimethylformamide.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.08-1.30 (m, 6H), 2.89 (d, 2H, J = 6.4 Hz), 3.28-3.67 (m, 2H), 3.95 (t, 1H, J = 10 Hz), 4.13 (q, 2H, J = 7.0 Hz), 4.62 (s, 4H), 6.64 (d, 2H, J = 8.6 Hz), 7.02 (d, 2H, J = 8.6 Hz), 7.19-7.40 (m, 10H). TS m/z (Cl): 418 (M+1).

(vi) Step: Ethyl-[(2S)-3-(4-aminophenyl)-2-ethoxypropanoate] (25via)

To a solution of 1.0 g (2.4 mmol) of compound (25va) in 20 ml of methanol was added 0.2 g of 10% palladium/carbon catalyst, and the mixture was hydrogenated in a Parr apparatus at room temperature and 413 kPa (60 psi) for 24 hours. The reaction mixture was filtered through celite, washing the filter pad with methanol. The combined filtrates were evaporated to dryness, and the residue was purified by chromatography on silica gel using 20% ethyl acetate in petroleum ether as eluent. 300 mg (53%) of the title compound was obtained. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.17 (t, 3H, J = 6.8 Hz), 1.23 (t, 3H, J = 7.0 Hz), 2.91 (d, 2H, J = 6.8 Hz), 3.25-3.79 (m, 2H), 3.95 (t, 1H, J = 6.8 Hz), 4.13 (q, 2H, J = 7.6 Hz), 6.62 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.3 Hz). TS m/z (Cl): 238 (M+1).

Ethyl [(2R)-3-(4-aminophenyl)-2-ethoxypropanoate] (25vib)

From 1.6 g (3.89 mmol) of compound (25vb) as described for the preparation of (25via) in 20 ml of methanol in the presence of 0.32 g of 10% palladium/carbon catalyst, 1.6 g (84%) of compound (25vib) was prepared. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.17 (t, 3H, J = 7.0 Hz), 1.23 (t, 3H, J = 7.0 Hz), 2.90 (d, 2H, J = 6.7 Hz), 3.25-3.80 (m, 2H), 3.94 (t, 1H, J = 6.7 Hz), 4.16 (q, 2H, J = 7.1 Hz), 6.61 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.1 Hz). TS m/z (Cl): 238 (M+1).

Example 26 (S)-Ethyl-[2-ethoxy-3-(4-aminophenyl)propionaph| (26) • · ·· ·· ··♦··««· ····*· · · « » · · · ♦ 71 .:..·..··-· :

Step (i): To a solution of 10 g (47.6 mmol) (S)-(4-nitrophenyl)glycine in 50 ml water, 60 ml 1 mol/l sulfuric acid and 150 ml acetone at -5°C, a solution of 9.85 g (142.8 mmol) sodium nitrite in 40 ml water was added dropwise over 30 min with stirring. The reaction mixture was stirred at -5°C to 0°C for 1.5 h and then at room temperature for 16 h. The acetone was removed and the reaction mixture was diluted with 500 ml ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by crystallization from isopropyl acetate to give 9.0 g (96%) of product. Op.: 134-136°C. [a] _D : -25° (c = 1.0, MeOH).

¹ H-NMR (CDCI ₃ ), δ 3.04 (dd, 1H, J = 14, 7.8 Hz), 3.24 (dd, 1H, J = 14, 4 Hz), 4.39 (dd, 1H, J = 7.3, 4.1 Hz), 7.42 (d, 2H, J = 8.7 Hz), 8.16 (d, 2H, J = 8.7 Hz) = 8.7 Hz).

IR (neat) cm' ¹ : 3485, 3180, 2927, 1715, 1515, 1343.

TS m/z(CI): 212 (M+1).

Step (ii): (S)-2-Hydroxy-3-(4-nitrophenyl)propanoic acid

9.0 g (42.6 mmol) of (S)-2-Hydroxy-3-(4-nitrophenyl)propanoic acid obtained as above were dissolved in 300 ml of anhydrous ethanol. 326 µl (5.9 mmol) of concentrated sulfuric acid were added to the solution and the reaction mixture was refluxed for 5-6 hours. The reaction mixture was neutralized with aqueous sodium bicarbonate solution, the ethanol was removed in a rotary evaporator and the residue was dissolved in ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate and evaporated. The crude product was crystallized from diisopropyl ether to give 8.0 g (78.5%) of the desired product. Op.: 74-76°C, [α] _D : -13° (c = 1.0, MeOH).

¹ H-NMR (CDCl3), δ: 1.30 (t, 3H, J = 7 Hz), 3.06 (dd, 1H, J = 14, 7 Hz), 3.25 (dd, 1H, J = 14, 3 Hz), 4.25 (q, 2H, J = 7 Hz), 4.25 (dd, 1H, J = 7, 4.3 Hz); 7.42 (d, 2H, J = 8.7 Hz), 8.16 (d, 2H, J = 8.7 Hz). IR (neat) cm' ¹ : 3432, 2924, 1736, 1518, 1347.

TS m/z(CI): 240 (M+1).

·· ·· ·· ······*· ··«·«· · · ,ι’. ·· «* (Hi) Step: To a mixture of 4.77 g (19.95 mmol) of (S)-ethyl-[2-hydroxy-3-(4-nitrophenyl)propionate] obtained in step (ii) above, 5.0 g of molecular sieves (4 Å) and 13.8 g (59.8 mmol) of powdered silver oxide in 100 ml of anhydrous acetonitrile at room temperature was added 6.4 ml (79.8 mmol) of ethyl iodide. The reaction mixture was heated at 60°C for 16 hours, then filtered through celite and the filtrate was evaporated. The crude product was chromatographed (ethyl acetate/hexane) to give 3.5 g (67% yield) of the desired product as a thick liquid. The 900 mg of unreacted starting material recovered can be reused. [α]d: -26° (c = 1.0, MeOH).

¹ H-NMR (CDCl3), δ: 1.15 (t, 3H, J = 7 Hz), 1.26 (t, 3H, j = 7.1 Hz), 3.10 (d, 1H, J = 3.8 Hz), 3.13 (s, 1H), 3.16-3.35 (m, 1H), 3.45-3.65 (m, 1H), 4.03 (dd, 1H, J = 7.5, 5.4 Hz), 4.21 (q, 2H, J = 7.2 Hz), 7.43 (d, 2H, J = 8.6 Hz), 8.15 (d, 2H, J = 8.6 Hz).

IR (neat) cm' ¹ : 2980, 1747, 1604, 1521, 1347. TS m/z (Cl): 268 (M+1).

(iv) Step: 6.0 g (25.3 mmol) of (S)-ethyl-[2-ethoxy-3-(4-nitrophenyl)propionate] obtained in step (iii) above was dissolved in 100 ml of anhydrous methanol. To the solution was added 2.0 g of 10% palladium/carbon catalyst and the mixture was hydrogenated under 138 kPa (20 psi) of hydrogen gas for 3-4 hours. The mixture was filtered through celite and the filtrate was evaporated to give a syrupy product in quantitative yield. [a] _D : -14.2° (c = 1.0, MeOH). Chiral HPLC: > 98 % ee.

¹ H-NMR (CDCl3), δ: 1.16 (t, 3H, J = 7.0 Hz), 1.22 (t, 3H, J = 7.0 Hz), 2.90 (d, 2H, J = 6.3 Hz), 3.30 (broad s, 2H, NH2), 3.24-3.42 (m, 1H), 3.50-3.70 (m, 1H), 3.94 (t, 1H, J = 6.3 Hz), 4.15 (q, 2H, J = 7.0 Hz), 6.62 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.0 Hz). IR (neat) cm' ¹ : 3372, 1738. TS m/z (Cl): 238 (M+1), 192 (M-OC 2 H ₅ ).

Example 27 (S)-Ethyl-[2-methoxy-3-(4-aminophenyl)propionate] (27) (i) Step: To a mixture of 12.5 g (52.3 mmol) of (S)-ethyl-[2-hydroxy-3-(4-nitrophenyl)propionate] obtained in Example 26 (ii) and 36.3 g (157 mmol) of powdered silver oxide in 260 ml of anhydrous acetonitrile at room temperature, 13 ml (209.2 mmol) of methyl iodide were added. 12.5 g of activated molecular sieves (4 A) were added to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was filtered through celite and the filtrate was evaporated. The crude product was purified by chromatography (ethyl acetate/hexane) to give 10.0 g (75%) of the desired compound as a thick liquid. [α] _D : -30.1° (c = 1.0, MeOH).

¹ H-NMR (CDCI ₃ ), δ: 1.24 (t, 3H, J = 7.1 Hz), 3.09 (d, 1H, J = 5.4 Hz), 3.12 (d, 1H, J = 2.7 Hz), 3.35 (s, 3H), 3.96 (dd, 1H, J = 7.5, 5.1 Hz), 4.19 (q, 2H, J = 7.1 Hz), 7.39 (d, 2H, J = 8.6 Hz), 8.13 (d, 2H, J = 8.6 Hz). IR (neat) cm' ¹ : 2995, 1747, 1604, 1521, 1343. TS m/z (Cl): 254 (M+1).

Step (ii): 8.0 g (31.6 mmol) of (S)-ethyl-[2-methoxy-3-(4-nitrophenyl)propionate] obtained in step (i) above was dissolved in 200 ml of anhydrous methanol, and 2.5 g of 10% palladium/carbon catalyst was added to the solution. The mixture was hydrogenated under 138 kPa (20 psi) of hydrogen gas for 3-4 hours. The reaction mixture was filtered through celite, the filtrate was evaporated to a syrup, and the crude product was purified by column chromatography (ethyl acetate/hexane) to give 7.0 g (100%) of the desired product as a thick liquid.

[a] _D : -14.1° (c = 1.0, MeOH). Chiral HPLC: > 98 % ee.

¹ H-NMR (CDCl 3 ), δ: 1.23 (t, 3H,J = 7.2 Hz), 2.91 (d, 2H, J = 6.1 Hz), 3.30 (broad, 2H, NH ₂ ), 3.34 (s, 3H), 3.88 (t, 1H, J = 6.2 Hz), 4.17 (q, 2H,J = 7.2 Hz), 6.62 (d, 2H, J = 8.3 Hz), 7.01 (d, 2H, J = 8.1 Hz). IR (neat) cm' ¹ : 3372, 2985, 2932, 1739, 1627, 1519. TS m/z (Cl): 223 (M), 234 (M+1), 192 (M-OMe).

Example 28 (S)-Ethyl-[2-ethoxy-3-(4-aminophenyl)propionate1 (28) (i) Step: 9.6 g (40.1 mmol) of (S)-ethyl-[2-hydroxy-3-(4-nitrophenyl)propionate] obtained as described in Example 26 (ii) was dissolved in 250 ml of ethyl acetate and 7.0 g of 10% palladium/carbon catalyst was added to the solution. The reaction mixture was hydrogenated under 138 kPa (20 psi) of hydrogen gas. The mixture was filtered through celite and the filtrate was concentrated to a syrup. The crude product was purified by column chromatography. · f”: ft · · w * · (ethyl acetate/hexane), 6.1 g (72%) of the desired product was obtained as a thick liquid. [a] _D : +6.5° (c = 1.0, MeOH).

¹ H-NMR (CDCI ₃ ), δ: 1.25 (t, 3H,J = 7.2 Hz), 2.83 (dd, 1 H,j = 14, 6.5 Hz), 2.98 (dd, 1H, J = 14, 4.6 Hz), 3.35 (broad s, 2H, NH ₂ ), 4.17 (q, 2H, J = 7.2 Hz), 4.33 (dd, 1H, J = 6.5, 4.6 Hz), 6.58 (d, 2H, J = 8.4 Hz), 6.97 (d, 2H, J = 8.1 Hz). IR (neat) cm' ¹ : 3372, 2985, 2932, 1739, 1627, 1519.

TS m/z (Cl): 209 (M), 210 (M+1).

(ii) Step: 4.0 g (19.1 mmol) of (S)-ethyl-[2-hydroxy-3-(4-aminophenyl)propionate] obtained in step (i) above was stirred in 100 ml of anhydrous dimethylformamide containing 4.7 ml (40.19 mmol) of benzyl bromide and 6.07 g (57.3 mmol) of sodium carbonate at room temperature for 16 hours. The reaction mixture was diluted with 300 ml of ethyl acetate, washed with 10% aqueous citric acid solution, dried over anhydrous sodium sulfate and evaporated. The product was purified by column chromatography (ethyl acetate/hexane) to give 4.5 g (61%) of the desired product as a thick liquid.

[a] _D : -12° (c = 1.0, MeOH). ¹ H-NMR (CDCI ₃ ), δ: 1.25 (t, 3H,J = 7.2 Hz), 2.16 (s, OH), 2.84 (dd, 1H, J = 14, 6.5 Hz), 2.99 (dd, 1H, J = 14, 4.6 Hz), 4.19 (q, 2H,J = 7.2 Hz), 4.31-4.37 (m, 1H), 4.62 (s, 4H), 6.66 (d, 2H, J = 8.8 Hz), 7.01 (d, 2H, J = 8.8 Hz), 7.21-7.35 (aromatic, 10H). IR (neat) cm' ¹ : 3497, 3062, 3028, 1733, 1615, 1521.

TS m/z (Cl): 390 (M+1).

(iii) Step: 4.5 g (1.0 equivalent weight, 11.57 mmol) of (S)-ethyl-[2-hydroxy-3-(4-dibenzylaminophenyl)propionate] obtained in step (ii) above is hydrolyzed in a methanol/tetrahydrofuran/water mixture at room temperature with 972 mg (2 equivalent weight, 23.1 mmol) of lithium hydroxide. water. The reaction mixture is evaporated and its pH is adjusted to pH = 3. The desired acid precipitates, which is filtered off to give 4.0 g (96%) of the desired product. M.p.: 114-116°C. ¹ H-NMR (CDCl ₃ ), δ: 2.83 (dd, 1H, J = 14, 7 Hz), 3.09 (dd, 1H, J = 14; 3.5 Hz), 4.35-4.44 (m, 1H), 4.62 (s, 4H), 6.68 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H,

-ί· . ώ. ·’> <

J = 8.3 Hz), 7.21-7.35 (aromatic, 10H). IR (neat) cm ^-1 : 3450, 3028, 2923, 1725, 1615, 1521. TS m/z (Cl): 362 (M+1).

Step (iv): 4.0 g (11.1 mmol) of (S)-[2-hydroxy-3-(4-dibenzylaminophenyl)propanoic acid] obtained as described in step (iii) above was dissolved in 56 ml of anhydrous dimethylformamide, and 886 mg (22.2 mmol) of sodium hydride (60% dispersion in oil) was added portionwise at room temperature. The reaction mixture was stirred at 50°C for 2 hours, then cooled to room temperature and 2.67 ml (33.3 mmol) of ethyl iodide was added. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate, washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 2.65 g (57%) of the desired product as a thick liquid. [α] _D : -3.5° (c = 1.0, MeOH).

¹ H-NMR (CDCl ₃ ), δ: 1.18 (t, 3H, J = 7.0 Hz), 1.20 (t, 3H, J = 7.3 Hz), 2.91 (d, 2H, J = 6.7 Hz), 3.30-3.48 (m, 1H), 3.52-3.70 (m, 1H), 3.97 (t, 1H, J = 6.7 Hz), 4.15 (q, 2H, J = 7.2 Hz), 4.62 (s, 4H), 6.67 (d, 2H, J = 8.3 Hz), 7.04 (d, 2H, J = 8.0 Hz), 7.23-7.36 (aromatic, 10H). IR (neat) cm' ¹ : 3027, 2978, 1744, 1616, 1521. TS m/z (Cl): 418 (M+1).

Step (v): The (S)-ethyl-[2-ethoxy-3-(4-dibenzylaminophenyl)propionate] obtained in step (iv) above is hydrogenated in ethyl acetate in the presence of 10% palladium on carbon catalyst under 140-210 kPa hydrogen gas (20-30 psi) for 3-4 hours. The catalyst is filtered off and the filtrate is evaporated to give the desired product. [a] _D : -14.2° (c = 1.0, MeOH). Chiral HPLC: > 98% ee. ¹ H-NMR (CDCl3), δ: 1.16 (t, 3H, J = 7.0 Hz), 1.22 (t, 3H, J = 7.0 Hz), 2.90 (d, 2H, J = 6.3 Hz), 3.30 (broad s, 2H, NH2), 3.243.42 (m, 1H), 3.50-3.70 (m, 1H), 3.94 (t, 1H,J = 6.3 Hz), 4.15 (q, 2H,J = 7.0 Hz), 6.62 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.0 Hz). IR (neat) cm' ¹ : 3372, 1738. TS m/z (Cl): 328 (M+1), 192 (M-OC 2 H ₅ ).

Example 29 (S)-Ethyl [2-methoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propionate] (29)

5.5 g (1.0 equivalent weight, 17.9 mmol) of 4-(3-methanesulfonyloxypropyl)phenylmethanesulfonate obtained as described in Example 1, 4.0 g (1.0 equivalent weight, 17.9 mmol) of (S)-[ethyl-2-methoxy-3-(4-aminophenyl)propionate] obtained as described in Example 27, 2.8 g (0.5 equivalent weight, 9.0 mmol) of tetrabutylammonium bromide and 7.4 g (3.0 equivalent weight, 53.7 mmol) of anhydrous potassium carbonate were heated with stirring in 90 ml of anhydrous toluene at 90°C for 7-9 hours. The reaction mixture was cooled with 300 ml of ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate, evaporated, and the residue was purified by chromatography (ethyl acetate/hexane) to give 3.4 g (44%) of the title compound as a viscous liquid. [α] _D : -6.5° (c = 1.0, MeOH).

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.26 (t, 3H, J = 7.0 Hz), 1.98 (quintet, 2H,J = 7.2 Hz), 2.75 (t, 2H, J = 7.6 Hz), 2.93 (d, 2H, J = 5.9 Hz), 3.02-3.22 (m, 5H), 3.37 (s,3H), 3.91 (t, 1H, J = 6.4 Hz), 4.20 (q, 2H, J = 7.0 Hz), 6.65 (d, 2H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.3 Hz), 7.15-7.3 (aromatic, 4H). IR (neat) cm ¹ : 3405, 2934, 2934, 1739, 1617, 1522, 1367. TS m/z (Cl): 435 (M). 436 (M+1).

Example 30

Ethyl-(2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenylpropionate] (30)

The title compound was prepared as described in Example 29 from 4-(3-methanesulfonyloxypropyl)phenylmethanesulfonate obtained as described in Example 1 and ethyl [2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 5 to give the desired product (40%) as a thick liquid.

¹ H-NMR (CDCl3, 200 MHz), δ: 1.16 (t, 3H, J = 5.8 Hz), 1.21 (t, 3H, J = 5.8 Hz), 1.91 (quintet, 2H, J = 7.2 Hz), 2.72 (t, 2H, J = 7.3 Hz), 2.88 (d, 2H, J = 7.3 Hz). 6.3 Hz), 3.02-3.18 (m, 5H), 3.22-3.42 (m, 1H), 3.42-3.62 (m, 1H), 3.93 (t, 1H, J = 6.5 Hz), 4.15 (q, 2H, J = 7.3 Hz), 6.51 (d, 2H, J = 8.3 Hz), 7.10 (d, 2H, J = 8.3 Hz), 7.15-7.24 (aromatic, 4H). IR (neat) cm ^-1 : 3400, 2978, 2934, 1738, 1616, 1502. TS m/z (Cl): 449 (M), 450 (M+1).

Example 31 (S)-Ethyl-[2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenylpropionate] (31)

The title compound was prepared as described in Example 29 from 4-(3-methanesulfonyloxypropyl)phenylmethanesulfonate obtained as described in Example 1 and (S)-ethyl-[2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 26. [α] ²⁵ D: -6.3° (1.0 MeOH). ¹ H-NMR (CDCl3, 200 MHz), δ: 1.16 (t, 3H, J = 5.8 Hz), 1.21 (t, 3H, J = 5.8 Hz), 1.91 (quintet, 2H, J = 7.2 Hz), 2.72 (t, 2H, J = 7.3 Hz), 2.88 (d, 2H, J = 7.3 Hz). 6.3 Hz), 3.02-3.18 (m, 5H), 3.22-3.42 (m, 1H), 3.42-3.62 (m, 1H), 3.93 (t, 1H, J = 6.5 Hz), 4.15 (q, 2H, J = 7.3 Hz), 6.51 (d, 2H, J = 8.3 Hz), 7.10 (d, 2H, J = 8.3 Hz), 7.15-7.24 (aromatic, 4H).

IR (neat) cm ¹ : 3400, 2978, 2934, 1738, 1616, 1502. TS m/z (Cl): 449 (M), 450 (M+1).

Example 32

Ethyl [2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propyloxycarbonylamino}phenylpropionate] (32)

The title compound was obtained as a by-product in 20% yield during the synthesis described in Example 30.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.14 (t, 3H, J = 7 Hz), 1.22 (t, 3H, J = 7 Hz), 1.98 (quintet, 2H, J = 7 Hz), 2.72 (t, 2H, J = 8 Hz), 2.95 (d, 2H, J = 6.1 Hz), 3.10 (s, 3H), 3.25-3.45 (m, 1H), 3.50-3.70 (m, 1H), 3.97 (t, 1H, J = 6.4 Hz), 4.05-4.24 (m, 4H), 6.68 (s, NH), 7.10-7.30 (aromatic, 8H). IR (neat) cm' ¹ : 3357, 2978, 1730, 1530. TS m/z (Cl): 494 (M+1).

Example 33

Ethyl-[2-ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}phenyl]propionate

I33)

The title compound was prepared according to the procedure described in Example 29 in 44% yield as a viscous liquid from 3-(3-methanesulfonyloxypropyl)phenylmethanesulfonate obtained as described in Example 2 and ethyl [2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 5. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.19 (t, 3H, J = 7.0 Hz), 1.25 (t, 3H, J = 7.0 Hz), 1.91 (quintet, 2H, J = 7.3 Hz), 2.78 (t, 2H, J = 7.8 Hz), 2.92 (d, 2H, J = 7.8 Hz). 6.7 Hz), 3.02-3.20 (m, 5H), 3.22-3.42 (m, 1H), 3.42-3.62 (m, 1H), 3.97 (t, 1H, J = 6.7 Hz), 4.19 (q, 2H, J = 7.2 Hz), 6.58 (d, 2H, J = 8.4 Hz), 6.64 (d, 2H, J = 8.4 Hz), 7.00-7.20 (aromatic, 3H), 7.22-7.40 (aromatic, 1H).

IR (neat) cm' ¹ : 3379, 2978, 2934, 1739, 1616, 1521.

TS m/z (Cl): 449 (M) 450 (M+1).

Example 34

Ethyl-r2-ethoxy-3-r4-{3-(4-(toluene-4-sulfonyloxy)phenyl)propylamino}phenyl1-propionate] (34)

The title compound was prepared as described in Example 29 in 77% yield as a viscous liquid from 4-(3-toluene-4-sulfonyloxy)propyl)phenyltoluene-4-sulfonate obtained as described in Example 3 and ethyl [2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 5.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.16 (t, 3H, J = 7.0 Hz), 1.22 (t, 3H, J = 7.2 Hz), 1.88 (quintet, 2H, J = 7.3 Hz), 2.43 (s, 3H), 2.67 (t, 2H, J = 7.4 Hz), 2.89 (d, 2H, J = 6.4 Hz), 3.08 (t, 2H, J = 7.0 Hz), 3.25-3.45 (m, 1H), 3.45-3.65 (m, 1H), 3.94 (t, 1H, J = 6.7 Hz), 4.15 (t, 2H, J = 7.2 Hz), 6.48 (d, 2H, J = 8.3 Hz), 6.87 (d, 2H, J = 8.3 Hz), 6.957.15 (aromatic, 4H), 7.28 (d, 2H, J = 8.3 Hz), 7.68 (d, 2H, J = 8.3 Hz).

IR (neat) cm' ¹ : 3407, 2927, 1741, 1616, 1521, 1502. TS m/z (Cl): 526 (M+1).

Example 35

Ethyl-[2-ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)propylamino}phenylpropionate (35}

The title compound was prepared as described in Example 29 in 35% yield as a viscous liquid from 4-(3-methanesulfonyloxypropyl)phenylmethanesulfonate obtained in Example 1 and ethyl [2-ethoxy-3-(3-aminophenyl)propionate] obtained in Example 7. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.16 (t, 3H, J = 7.0 Hz), 1.22 (t, 3H, J = 7.0 Hz), 1.92 (quintet, 2H, J = 7.3 Hz), 2.73 (t, 2H, J = 7.6 Hz), 2.92 (d, 2H, J = 7.6 Hz). 6.5 Hz), 3.02-3.22 (m, 5H), 3.22-3.42 (m, 1H), 3.42-3.62 (m, 1H), 4.00 (t, 1H, J - 6.5 Hz), 4.16 (q, 2H, J = 7.0 Hz), 6.40-6.62 (aromatic, 3H), 7,007.30 (aromatic, 5H). IR (neat) cm' ¹ : 3406, 2978, 2934, 1740, 1606, 1503.

TS m/z (Cl): 450 (M+1), 449 (M).

Example 36

Ethyl-[2-isopropoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propionate (36)

The title compound was prepared as described in Example 29 in 47% yield as a viscous liquid from 4-(3-methanesulfonyloxypropyl)phenylmethanesulfonate obtained as described in Example 1 and ethyl [2-isopropoxy-3-(4-aminophenyl)propionate] obtained as described in Example 9. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 0.99 (d, 3H, J = 6.0 Hz), 1.16 (d, 3H, J = 6.3 Hz), 1.24 (t, 3H, J = 7.3 Hz), 1.93 (quintet, 2H, J = 7.3 Hz), 2.74 (t, 2H, J = 7.3 Hz). 7.8 Hz), 2.80-2.90 (m, 2H), 3.02-3.20 (m, 5H), 3.50 (apparent quintet, 1H, J = 6.0 Hz), 3.99 (dd, 1H, J = 7.8 and 5.3 Hz), 4.17 (q, 2H, J = 7.3 Hz), 6.52 (d, 2H, J = 8.3 Hz), 7.05 (d, 2H, J = 8.3 Hz).

IR (neat) cm' ¹ : 3406, 2974, 2939, 1739, 1616, 1522.

TS m/z (Cl): 464 (M+1).

Example 37

Ethyl [2-ethoxy-3-[4-(4-methylsulfonylphenethylamino)phenyl]propionate (37) , 80 · ^: ·· · ^! ·· '··'

0.3 g (1.27 mmol) of ethyl [2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 5 and 0.437 g (3.16 mmol) of anhydrous potassium carbonate in 10 ml of toluene were stirred at room temperature for 30 minutes. 0.484 g (1.65 mmol) of 4-(2-methylsulfonyloxyethyl)phenylmethanesulfonate obtained as described in Example 12 in 5 ml of toluene were added dropwise to the above reaction mixture, followed by the addition of 81 mg (0.25 mmol) of tetrabutylammonium bromide. The reaction mixture was stirred at 90°C for 30 hours, then cooled to room temperature, diluted with 50 ml of ethyl acetate and washed with water. The aqueous phase was extracted with 2 x 50 ml ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give 0.24 g (44%) of the title compound as a pale yellow oil. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.17 (t, 3H,J = 7.1 Hz), 1.24 (t, 3H, J = 6.4 Hz), 2.91 (d, 2H, J = 6.8 Hz), 2.93 (t, 2H, J = 7.1 Hz), 3.15 (s, 3H), 3.32-3.34 (m, 3H), 3.50-3.67 (m, 1H), 3.96 (t, 1H, J = 6.6 Hz), 4.18 (q, 2H, J = 7.3 Hz), 6.59 (d, 2H, J = 8.3 Hz), 7.08 (d, 2H, J = 8.3 Hz), 7.19-7.30 (m, 4H). TS m/z (Cl): 436 (M+1).

Example 38 (S)-Ethyl-[2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propanoate] (38)

2.5 g (10.55 mmol) of (S)-ethyl-[2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 26 and 4.37 g (31.65 mmol) of anhydrous potassium carbonate in 20 ml of toluene were stirred at room temperature for 30 minutes. 4.03 g (13.71 mmol) of 4-(2-methylsulfonyloxyethyl)phenylmethanesulfonate obtained as described in Example 12 in 10 ml of toluene were added dropwise to the reaction mixture, followed by the addition of 0.34 g (1.055 mmol) of tetrabutylammonium chloride. The reaction mixture was stirred at 90-100°C for 30 hours, then cooled to room temperature, diluted with 100 ml of ethyl acetate and washed with water. The aqueous phase was extracted with 2x50 ml of ethyl acetate, the combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give 0.31 g (6.7%) of the title compound as a yellow oil. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.17 (t, 3H, J = 6.8 Hz), 1.26 (t, 3H, J = 7.0 Hz), 2.88-3.02 (m, 4H), 3.15 (s, 3H), 3.28-3.45 (m, 3H, 9, 3.50-3.70 (m, 1H), 3.95 (t, 1H, J = 6.6 Hz), 4.17 (q, 2H, J = 7.2 Hz), 6.67 (d, 2H, J = 8.3 Hz), 7.10 (d, 2H, J = 8.0 Hz), 7.18-7.30 (m, 4H) TS m/z (Cl): 436 (M+1).

Example 39

Ethyl-[2-ethoxy-3-{4-nE)-3-(4-methylsulfonyloxyphenyl)-2-propenylaminolphenyl}-propionate] (39)

Following the procedure described in Example 37, 150 mg (28.4%) of the title compound was prepared from 0.43 g (1.41 mmol) of 4-[(E)-3-chloro-1-propenyl]phenyl methanesulfonate prepared as described in Example 22, 0.28 g (1.18 mmol) of ethyl [2-ethoxy-3-(4-aminophenyl)propionate] prepared as described in Example 5 in 25 mL of toluene using 489 mg (3.54 mmol) of potassium carbonate and 38 mg (0.118 mmol) of tetrabutylammonium bromide over 30 hours. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.17 (t, 3H, J = 7.1 Hz), 1.22 (t, 3H, J = 7.1 Hz), 2.91 (d, 2H, J = 6.3 Hz), 3.14 (s, 3H), 3.26-3.44 (m, 1H), 3.51-3.68 (m, 1H), 3.93 (d, 2H, J = 6.3 Hz), 3.95 (t, 1H,J = 6.6 Hz), 4.16 (q, 2H, J = 7.1 Hz), 6.23-6.39 (m, 1H), 6.56-6.64 (m, 3H), 7.07 (d, 2H, J = 8.3 Hz), 7.22 (d, 2H, J = 8.3 Hz), 7.40 (d, 2H, J = 8.3 Hz). TS m/z (Cl): 402 (M+1).

Example 40 (S)-Ethyl-r2-ethoxy-3-(4-r(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino-1-phenyl}-propionate) (40)

5.2 g (31.8%) of the title compound were prepared according to the procedure described in Example 38 from 15.90 g (52.1 mmol) of 4-[(E)-3-chloro-1-propenyl]phenyl methanesulfonate obtained as described in Example 22 and 9.5 g (40.1 mmol) of (S)-ethyl-[2-ethoxy-3-(4-aminophenyl)propionate] prepared as described in Example 26 by reacting the reagents for 24 hours in 150 ml of toluene in the presence of 16.6 g (120.25 mmol) of potassium carbonate and 1.29 g (4.01 mmol) of tetrabutylammonium bromide. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.17 * . · ·· · · 82 .:...1.. ·..· -· :

(t, 3H, J = 7.2 Hz), 1.22 (t, 3H, J = 7.3 Hz), 2.90 (d, 2H, J = 6.4 Hz), 3.13 (s, 3H), 3.26-3.44 (m, 1H), 3.51-3.68 (m, 1H), 3.90-4.00 (m, 3H), 4.16 (q, 2H, J = 7.2 Hz), 6.28 (td, 1H, J = 5.4 and 16.1 Hz), 6.57-6.64 (m, 3H), 7.06 (d, 2H, J = 8.3 Hz), 7.21 (d, 2H, J = 8.6 Hz), 7.39 (d, 2H, J = 8.6H). TS m/z (Cl): 448 (M ⁺ +1), 402 (M+1-OEt).

Example 41

Methyl [2-ethoxy-3-[4-(4-methanesulfonyloxybenzylamino)phenyl]propionate (41)

500 mg (1 equivalent, 2.5 mmol) of 4-methanesulfonyloxybenzaldehyde obtained as described in Example 10, 557 mg (equivalent, 2.5 mol) of methyl-[2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 6, activated molecular sieve (4 Å) and 43 mg (0.1 equivalent, 0.25 mmol) of p-TsOH were stirred in 15 ml of dichloromethane at room temperature for 16 hours. The reaction mixture was diluted with 100 ml of ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, concentrated in a rotary evaporator and dried under reduced pressure. The crude product was dissolved in 15 ml of anhydrous methanol and 250 µl of concentrated hydrochloric acid was added at 0°C, followed by 188 mg (1.2 equivalents, 3.0 mmol) of sodium borocyanohydride in portions. The reaction mixture was stirred at 0°C for 3 hours and then diluted with 100 ml of ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate, dried over sodium sulfate and evaporated. The residue was purified by chromatography using ethyl acetate/hexane as eluent. 950 mg (37%) of the title compound was obtained as a viscous oil. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.16 (t, 3H, J = 6.9 Hz), 2.90 (d, 2H, J = 6.8 Hz), 3.14 (s, 3H), 3.22-3.41 (m, 1H), 3.44-3.62 (m, 1H), 3.70 (s, 3H), 3.97 (t, 1H, J = 6.6 Hz), 4.33 (s, 2H), 6.54 (d, 2H, J = 8.3 Hz), 7.04 (d, 2H, J = 8.3 Hz), 7.25 (d, 2H, J = 8.3 Hz), 7.41 (d, 2H, J = 8.3 Hz). IR (neat) cm ^-1 : 3412, 2932, 1744, 1616, 1522, 1503. TS m/z (Cl): 408 (M+1), 407 (M).

Example 42

·.*:·<· (S)-2-IVIethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino1-phenyl]-propanoic acid (42)

3.4 g (1.0 equivalent weight, 7.8 mmol) of (S)-ethyl-[2-methoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}-phenyl]propionate] obtained as described in Example 29 is hydrolyzed in a methanol/tetrahydrofuran/water mixture at room temperature with 492 mg (1.5 equivalent weight, 11.7 mmol) of lithium hydroxide water for 3-4 hours. The reaction mixture is concentrated, diluted with water and its pH is adjusted to pH = 3 with aqueous hydrochloric acid. The desired acid precipitates from the aqueous phase, the precipitate is collected by filtration. If the precipitated acid is not sufficiently pure according to thin layer chromatography tests, purification is carried out by chromatography using methanol and chloroform as eluent. 2.5 g (79%) of pure acid were obtained as a white solid. M.p.: 90-92°C. [α] _D : -16° (c = 1.0, MeOH). ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.25 (s, 1H, NH), 1.94 (quintet, 2H, J = 7.2 Hz), 2.72 (t, 2H, J = 7.8 Hz), 2.82-3.02 (m, 2H), 3.02-3.18 (m, 5H), 3.38 (s, 3H), 3.97 (t, 1H,J = 4.8 Hz), 4.90 (broad s, CO2H), 6.58 (d, 2H, J = 8.1, Hz), 7.05 (d, 2H, J = 8.3 Hz), 7.15-7.24 (aromatic, 4H). ¹³ C-NMR (CDCl 3 , 50 MHz), δ: 29.53, 32.34, 37.15 (2C), 46.48, 57.58, 82.07, 116.31, 121.90, 129.75, 130.39, 140.57, 142.48, 147.33, 175.87. IR (neat) cm' ¹ : 3046, 2932 1732, 1615, 1520, 1365. TS m/z (Cl): 408 (M+1), 407 (M).

Example 43

2-Ethoxy-3-(4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenypropanoic acid (43)

The title compound was prepared as described in Example 42 by hydrolyzing ethyl [2-(ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propionate] obtained as described in Example 30 with lithium hydroxide. M.p.: 120-122°C.

¹ H-NMR (CDCl3, 200 MHz), δ: 1.18 (t, 3H, J = 7.1 Hz), 1.25 (s, 1H, NH), 1.93 (quintet, 2H, J = 6.9 Hz), 2.74 (t, 2H, J = 7.5 Hz), 2.80-3.02 (m, 2H), 3.02-3.18 (m, 5H), 3.40-3.62 (m, 2H), 4.03 (dd, 1H, J = 6.9, 4.4 Hz), 4.07 (broad s, CO ₂ H), 7.05 (d, 2H, J = 8.3 Hz), 7.22 (d, 2H, J = 8.3 Hz), 7.15-7.24 (aromatic, 4H).

IR (neat) cm' ¹ : 3389, 2925, 1616, 1502. TS m/z (Cl): 422 (M+1).

Example 44

2zEthoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propyloxycarbonyl)amino}phenylpropanoic acid (44)

The title compound was prepared as described in Example 42 by hydrolyzing ethyl (2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propyloxycarbonylamino}phenyl]propionate] obtained as described in Example 32 with lithium hydroxide. The product was characterized by high-flow ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.19 (t, 3H, J = 7 Hz), 2.01 (q, 2H, J = 7 Hz), 2.75 (t, 2H, J = 7.5 Hz), 2.90-3.10 (m, 2H), 3.13 (s, 3H), 3.35-3.55 (m, 1H), 3.55-3.75 (m, 1H), 4.08 (dd, 1H, J = 7, 4.8 Hz), 4.21 (t, 2H, J = 6.3 Hz), 6.85 (broad, NH), 7.107.35 (aromatic, 8H), 8.4 (broad s, -COOH). IR (neat) cm' ¹ : 3334, 3021, 2935, 1723, 1528.

Example 45 (S)-2-Ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl-1-propanoic acid (45)

The title compound was prepared as described in Example 42 by hydrolyzing (S)-ethyl-[2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propionate] obtained as described in Example 31 with lithium hydroxide. [α] ²⁵ _D : -16° (c = 1.0, MeOH). ¹ H-NMR (CDCl3, 200 MHz), δ: 1.18 (t, 3H, J = 7.1 Hz), 1.25 (s, 1H, NH), 1.93 (quintet, 2H, J = 6.9 Hz), 2.74 (t, 2H, J = 7.5 Hz), 2.80-3.02 (m, 2H), 3.02-3.18 (m, 5H), 3.40-3.62 (m, 2H), 4.03 (dd, 1H, J = 6.9, 4.4 Hz), 4.07 (broad s, CO2H), 7.05 (d, 2H, J = 8.3 Hz), 7.22 (d, 2H, J = 8.3 Hz), 7.15-7.24 (aromatic, 4H).

IR (neat) cm ¹ : 3389, 2925, 1616, 1502. TS m/z (Cl): 422 (M+1).

Example 46

2-Ethoxy-3-[4-[3-(3-methanesulfonyloxyphenyl)propylamino]phenyl]-1-propanoic acid (46)

The title compound was prepared as described in Example 42 in 73% yield as a viscous liquid by hydrolysis with lithium hydroxide from 2-ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}phenyl]propionate] prepared as described in Example 33. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.19 (t, 3H, J = 7.1 Hz) 1.25 (s, 1H, NH), 1.90-2.02 (quintet, 2H, J = 6.9 Hz), 2.76 (t, 2H, J = 7.9 Hz), 2.803.05 (m, 2H), 3.05-3.20 (m, 5H), 3.40-3.62 (m, 2H), 4.03 (dd, 1H, J = 6.9 and 4.4 Hz), 4.60 (broad s, CO2H), 6.58 (d, 2H, J = 8.3 Hz), 7.00-7.20 (aromatic H), 7.22-7 29 (aromatic, 1H). IR (neat) cnT ¹ : 3406, 2931, 1613, 1521. TS m/z (Cl): 422 (M+1).

Example 47

2-Ethoxy-3-[4-{3-(4-(toluene-4-sulfonyloxy)phenyl)propylamino}phenyl]propanoic acid

310 mg (72%) of the title compound were prepared as a solid according to the procedure described in Example 42 by hydrolyzing ethyl [2-ethoxy-3-[4-{3-(4-(toluene-4-sulfonyloxy)phenyl)propylamino}phenyl]propionate] obtained as described in Example 34 with lithium hydroxide. M.p.: 98-100°C.

H-NMR (CDCl3, 200 MHz), δ: 1.16 (t, 3H, J = 6.8 Hz), 1.88 (quintet, 2H, J = 7.3 Hz) 2.42 (s, 3H), 2.66 (t, 2H, J = 6.9 Hz), 2.80-3.30 (m, 4H), 3.35-3.65 (m, 2H), 4.01 (dd, 1H, J = 7.1,4.4 Hz), 4.40 (broad, OH, NH), 6.53 (d, 2H, J = 8.3 Hz), 6.86 (d, 2H, J = 8.3 Hz), 7.00-7.10 (aromatic, 4H), 7.28 (d, 2H, J = 8.3 Hz). 8.3 Hz), 7.68 (d, 2H, J = 8.3 Hz). IR (neat) cm' ¹ :. 3411, 2925, 1731, 1618, 1525, 1502. TS m/z (Cl): 498 (M+1).

Example 48

2-Ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propanoic acid (48)

500 mg of the title compound (67) was prepared as a viscous liquid by the method described in Example 42 by hydrolyzing 800 mg (1.01 equivalent weight, 1.78 mmol) of ethyl [2-ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propionate] obtained as described in Example 35 with lithium hydroxide. ¹ H-NMR (CDCl3, 200 MHz), δ: 1.16 (t, 3H, J = 7.0 Hz), 1.92 (quintet, 2H, J = 7.3 Hz), 2.73 (t, 2H, J = 7 6 Hz), 2.90 (dd, 1H, J = 14 and 7.5 Hz), 3.08 (dd, 1H, J = 14 and 7.5 Hz = 14, 4.3 Hz), 3.02-3.20 (m, 5H), 3.32-3.50 (m, 1H), 3.50-3.68 (m, 1), 4.07 (dd, 1H, J = 7.5, 4.3 hz), 4.16 (q, 2H, J = ··«*<· · * 86 .;λ.ΰ. <?·-'· :*

7.0 Hz), 6.42-6.62 (aromatic, 3H), 7.00-7.30 (aromatic, 5H). IR (neat) cm ^-1 : 3500, 3021 2936, 1723, 1607, 1504. TS m/z (Cl): 422 (M+1).

Example 49

2-Isopropoxy-3-r4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenylH-propionic acid (49)

The title compound was obtained in 74% yield as a white solid by hydrolyzing 300 mg (1.0 equivalent weight, 0.65 mmol) of ethyl [2-isopropoxy-3-[4-{3-(4-ethanesulfonyloxyphenyl)propylamino}phenyl]propionate] obtained as described in Example 36 with lithium hydroxide.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.04 (d, 3H, J = 6.3 Hz), 1.16 (d, 3H,J = 6.0 Hz), 1.25 (s, 1H, NH), 1.93 (quintet, 2H, J = 7.3 Hz), 2.74 (t, 2H,J = 7.8 Hz), 2.87 (dd, 1H, J = 14.2 and 7.9 Hz), 3.01 (dd, 1H,J — 14.1, 3.4 Hz), 3.05-3.20 (m, 5H), 3.55 (apparent quintet, 1H, J = 6.0 Hz), 4.07 (dd, 1H, J = 7.9 and 3.4 Hz), 4.17 (q, 2H, J = 7.3 Hz), 4.90 (broad s, CO ₂ H), 6.52 (d, 2H, J = 8.3 Hz), 7.04 (d, 2H, J = 8.3 Hzh).

IR (neat) cm' ¹ : 3406, 1974, 2939, 1739, 1616, 1522. TS m/z (Cl): 436 (M+1).

Example 50

2-Ethoxy-3-(4-(4-methanesulfonyloxybenzylamino)phenyl)propionic acid (50)

400 mg (83%) of the title compound as a viscous liquid were prepared by the procedure described in Example 42 by hydrolyzing 500 mg (1.0 equivalent weight, 1.2 mmol) of methyl [2-ethoxy-3-[4-(4-methanesulfonyloxybenzylamino)phenyl]propionate] obtained as described in Example 41 with lithium hydroxide. ¹ H-NMR (CDCl ₃ , 200 MHz), 6:1.16 (t, 3H, J = 6.8 Hz), 2.87 (dd, 1H, J = 14.1 and 7.3 Hz), 2.99 (dd, 1H, J = 14.1 and 4.4 Hz), 3.11 (s, 3H), 3.28-3.62 (m, 2H), 4.00 (dd, 1H, J = 7.3, 4.4 Hz), 4.30 (s, 2H), 5.23 (broad s, NH), 6.53 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.3 Hz), 7.22 (d, 2H, J = 8.3 Hz), 7.39 (d, 2H, J =8.3 Hz). IR (neat) cm' ¹ : 3397, 2977, 2932, 1730, 1615, 1522, 1503. TS m/z (Cl): 422 (M+1).

Example 51

2-Ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propionic acid (51)

To a solution of 0.22 g (0.51 mmol) of ethyl-[2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propionate] obtained as described in Example 37 in 10 ml of methanol was added a solution of 268 mg (2.53 mmol) of sodium carbonate in 5 ml of water, and the reaction mixture was stirred at room temperature for 36 hours. The methanol was evaporated under reduced pressure, the residue was diluted with 20 ml of water. The aqueous phase was washed with 50 ml of ethyl acetate, then the pH was adjusted to about 4 with 2N hydrochloric acid solution, and extracted with 2x50 ml of ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography using 50% ethyl acetate/petroleum ether as eluent to give 80 mg (39%) of the title compound.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.19 (t, 3H, J = 6.8 Hz), 2.82-3.05 (m, 4H), 3.15 (s, 3H), 3.40 (t, 3H, J = 7.2 Hz), 3.45-3.62 (m, 1H), 4.01-4.10 (m, 1H), 6.63 (d, 2H, J = 8.3 Hz), 7.08 (d, 2H, J = 8.4 Hz), 7.18-7.30 (m, 4H). TS m/z (Cl): 408 (M+1).

Example 52 (S)-2-Ethoxy-3-[4-(4-methanesulfonyloxyphenethylamino)phenyl-1-propionic acid (52)

As described in Example 51, 0.34 g (0.78 mmol) of ethyl [(S)-2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propionate] obtained as described in Example 38 was hydrolyzed in 5 ml of methanol with a solution of 414 mg (3.91 mmol) of sodium carbonate in 5 ml of water at room temperature for 24 hours to give 180 mg (57.6%) of the title compound. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.19 (t, 3H, J = 7.0 Hz), 2.48-3.03 (m, 4H), 3.14 (s, 3H), 3.39 (t, 3H, J = 7.0 Hz), 3.42-3.61 (m, 2H), 4.04 (dd, 1H, J = 4.4 and 7.1 Hz), 6.55 (d, 2H, J = 8.3 Hz), 7.05 (d, 2H, J = 8.3 Hz), 7.22-7.27 (m, 4H). TS m/z (Cl): 408 (M+1).

Example 53

1:.1:. ·::··-· s' (S)-2-Ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]-phenyl}-propionic acid (53) g (8.95 mmol) ethyl [2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]-phenyl}-propionate] obtained as described in Example 40 was hydrolyzed with 563 mg (13.42 mmol) lithium hydroxide in a 45:4:9 methanol/tetrahydrofuran/water mixture (58 ml) as described in Example 42 to give 1.2 g (32%) of the title compound. [a] ²⁵ _D : -18°C (c = 0.1, MeOH). M.p.: 156-158°C.

¹ H-NMR (CD ₃ OD, 200 MHz), δ: 1.11 (t, 2H, J = 6.8 Hz), 2.74-2.98 (m, 2H), 3.19 (s, 3H), 3.25-3.70 (m, 2H), 3.88-4.02 (m, 3H), 6.36 (td, 1H,J = 16.1 and 5.4 Hz), 6.62-6.75 (m, 3H), 7.02 (d, 2H, J = 7.8 Hz), 7.24 (d, 2H, J = 8.3 Hz), 7.45 (d, 2H, J = 8.8 Hz). TS m/z (Cl): 420 (M+1).

Example 54

Ethyl-2-ethoxy-3-[4-(4-methylsulfonyloxybenzylcarboxamido)phenylpropionate] (54)

To a cooled solution of 0.53 g (2.3 mmol) of 2-(4-methylsulfonyloxyphenyl)acetic acid obtained as described in Example 14 in 25 ml of dichloromethane was slowly added 311 mg (2.30 mmol) of HOBt followed by 442 mg (2.30 mmol) of EDC and the reaction mixture was stirred for 10 minutes. 601 mg (2.535 mmol) of ethyl [2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 5 was added to the above reaction mixture and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/petroleum ether 1:3) to give 710 mg (69%) of the title compound. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.13 (t, 3H, J = 7.1 Hz), 1.23 (t, 3H, J = 7.1 Hz), 2.95 (d, 2H, J = 5.9 Hz), 3.16 (s, 3H), 3.21-3.41 (m, 1H), 3.51-3.67 (m, 1H), 3.71 (s, 2H), 3.95 (t, 1H, J = 6.6 Hz), 4.16 (q, 2H, J = 6.8 Hz), 7.09-7.43 (m, 8H). TS m/z (Cl): 450 (M + 1).

Example 55 » ♦ ·· · · *

2-Ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]-phenyl}-propionic acid (55)

140 mg (0.313 mmol) of ethyl-[2-ethoxy-3-{4-[( E )-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]phenyl}-propionate] obtained as described in Example 39 was hydrolyzed with 17 mg (0.407 mmol) of lithium hydroxide in 6 ml of a 2:1 methanol/water mixture according to the procedure described in Example 42 to give 40 mg (30.5%) of the title compound. M.p.: 146-148°C. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.12 (t, 3H, J = 6.6 Hz), 2.72-3.00 (m, 2H), 3.20 (s, 3H), 3.25-3.42 (m, 2H), 3.50-3.68 (m, 1H), 3.88-4.00 (m, 2H), 6.30-6.48 (m, 1H), 6.60-6.70 (m, 3H), 7.04 (d, 2H, J = 7.3 Hz), 7.25 (d, 2H, J = 7.8 Hz), 7.47 (d, 2H, J = 8.3 Hz).

Example 56

2-Ethoxy-3-[4-(4-methylsulfonyloxybenzylcarboxamido)phenylpropionic acid (56)

0.7 g (1.56 mmol) of ethyl [2-ethoxy-3-[4-(4-methylsulfonyloxybenzylcarboxamido)phenyl]propionate] obtained as described in Example 54 was hydrolyzed with sodium carbonate in 20 ml of methanol/water 3:1 at room temperature for 60 hours following the procedure described in Example 51. 220 mg (33.5%) of the title compound was obtained as a white solid. M.p.: 162-164°C.

¹ H-NMR (CDCI ₃ , + DMSO-de, 200 MHz), δ: 1.14 (t, 3H, J = 7.0 Hz), 2.84-3.10 (m, 2H), 3.15 (s, 3H), 3.25-3.40 (m, 1H), 3.55-3.67 (m, 1H), 3.70 (s, 2H), 3.95 (dd, 1H, J = 4.7 and 7.9 Hz), 7.18-7.52 (m, 8H). TS m/z (Cl): 422 (M+1).

Example 57

Ethyl-[2-ethoxy-3-[4-{3-(4-tert-butoxy-4-methylsulfonamidophenyl)propylamino}phenyl]propionate (57)

0.29 g (1.22 mmol) of ethyl [2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 5 and 506 mg (3.67 mmol) of potassium carbonate were stirred in 20 ml of toluene at room temperature for 30 minutes. 0.6 g (1.47 mmol) of 3-(4-tert-butoxy-4-methylsulfonylamidophenyl)propylmethanesulfonate obtained as described in Example 19 were stirred in 10 ml of toluene.

in toluene is added dropwise to the above reaction mixture, followed by the addition of 39 mg (0.122 mmol) of tetrabutylammonium bromide. The reaction mixture is stirred at 90-100°C for 40 hours, then cooled to room temperature, diluted with 100 ml of ethyl acetate and washed with brine. The aqueous phase is extracted with ethyl acetate, the combined organic phase is washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (190 mg (28.3%) of the title compound. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.16 (t, 3H, J = 6.8 Hz), 1.26 (t, 3H, J = 7.2 Hz), 1.50 (s, 9H), 1.64-1.82 (m, 2H), 2.59 (t, 2H, J = 7.6 Hz), 2.84 (s, 3H), 3.02 (d, 2H, J = 6.7 Hz), 3.26-3.42 (m, 1H), 3.55-3.70 (m, 3H), 4.02 (t, 1H, J = 6.6 Hz), 4.19 (q, 2H, J = 6.2 Hz), 6.39 (broad s, 1H, _D2O exchangeable), 7.00 (d, 2H, J=8.3 Hz), 7.20-7.34 (m, 6H). TS m/z (Cl): 548 (M).

Example 58

2-Ethoxy-3-(4-{3-(4-tert-butoxy-4-methylsulfonamidophenyl)propylamino}phenyl)propionic acid (58)

180 mg (0.33 mmol) of ethyl-[2-ethoxy-3-[4-{3-(4-tert-butoxy-4-methylsulfonamidophenyl)propylamino}-phenylpropionate] obtained as described in Example 57 was hydrolyzed with 18 mg (0.43 mmol) of lithium hydroxide in 6 ml of a 2:1 methanol/water mixture at room temperature overnight. The reaction mixture was concentrated, diluted with water and adjusted to pH = 4 with aqueous hydrochloric acid. The crude acid was extracted with ethyl acetate, the ethyl acetate phase was dried over sodium sulfate, concentrated and purified by chromatography (ethyl acetate/petroleum ether 1:1) to give 140 mg (82%) of the desired compound as a white solid. M.p.: 78-80°C.

¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.21 (t, 3H, J = 6.8 Hz), 1.51 (s, 9H), 1.70-1.88 (m, 2H), 2.60 (t, 2H, J = 7.3 Hz), 2.85 (s, 3H), 3.00-3.22 (m, 2H), 3.38-3.70 (m, 4H), 4.084.20 (m, 1H), 6.48 (broad s, 1H, D ₂ O exchangeable), 7.97 (d, 2H, J = 8.3 Hz), 7.20-7.35 (m, 6H).

Example 59 , * ·' **» * · 91 -•'w' 5

Ethyl-r2-ethoxy-3-{4-f(E)-2-(4-methylsulfonyloxyphenyl)-1-ethenylcarboxamidolphenylpropionate] (59)

From a mixture of 0.5 g (2.07 mmol) of (E)-3-(4-methylsulfonyloxyphenyl)-2-propenoic acid obtained as described in Example 23, 279 g (2.07 mmol) of HOBt, 396 mg (2.07 mmol) of EDC and 539 mg (2.273 mmol) of ethyl [2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 5 in 25 ml of dichloromethane, 0.24 g (25.2%) of the title compound was prepared according to the procedure described in Example 54 at room temperature within 48 hours. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.17 (t, 3H,J = 7.0 Hz), 1.27 (t, 3H,J = 7.1 Hz), 3.00 (d, 2H, J = 6.2 Hz), 3.19 (s, 3H), 3.28-3.45 (m, 1H), 3.55-3.70 (m, 1H), 4.01 (t, 1H, J = 6.6 Hz), 4.16 (q, 2H, J = 56.3 Hz), 6.54 (d, 1H, J = 15.3 Hz), 7.20-7.35 (m, 4H), 7.50-7.60 (m, 4H), 7.72 (d, 1H, J = 15.6 Hz). TS m/z (Cl): 462 (M+1).

Example 60

2-Ethoxy-3-{4-[(E)-2-(4-methylsulfonyloxyphenyl)-1-ethenylcarboxamidolphenyl}-propanoic acid (60)

According to the procedure described in Example 51, ethyl [2-ethoxy-3-{4-[(E)-2-(4-methylsulfonyloxyphenyl)-1-ethenylcarboxamido]phenyl}-propionate] obtained as described in Example 59 was hydrolyzed with a solution of 230 mg (2.17 mmol) of sodium carbonate in 5 ml of water in 10 ml of methanol at room temperature for 48 hours to give 35 mg (18.6%) of the title compound as a white solid. M.p.: 178-180°C.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.15 (t, 3H, J = 7.0 Hz), 2.84-3.10 (m, 2H), 3.22 (s, 3H), 3.22-3.42 (m, 1H), 3.55-3.72 (m, 1H), 3.97 (dd, 1H, J = 4.8 and 8.0 Hz), 6.80 (d, 1H, J = 15.6 Hz), 7.20-7.35 (m, 4H), 7.50-7.70 (m, 5H). TS m/z (Cl): 434 (M+1).

Example 61

Ethyl-r2-ethoxy-344-(4-methylsulfonyloxyphenethylcarboxamido)-phenine propionate 1611

According to the procedure described in Example 54, 0.5 g (2.49 mmol) of 3-(4-methylsulfonyloxyphenyl)propanoic acid obtained as described in Example 24 was treated in 25 ml of dichloromethane with 277 mg (2.049 mmol) of HOBt, 393 mg (2.049 mmol) of EDC and 534 mg (2.254 mmol) of ethyl [2-ethoxy-3-(4-aminophenyl)propionate] obtained as described in Example 5 to give 0.5 g (52.7%) of the title compound as a white solid. M.p.: 90-92°C. ¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.15 (t, 3H,J = 7.0 Hz), 1.24 (t, 3H, J = 7.5 Hz), 2.64 (t, 2H, J = 7.5 Hz), 2.96 (d, 2H, J = 6.4 Hz), 3.07 (t, 2H, J = 6.4 Hz) 7.5 Hz), 3.12 (s, 3H), 3.25-3.42 (m, 1H), 3.52-3.66 (m, 1H), 3.97 (t, 1H, J = 6.4 Hz), 4.17 (q, 2H, J = 7.2 Hz), 7.18-7.42 (m, 8H). TS m/z (Cl): 464 (M+1).

Example 62

2-Ethoxy-3-(4-(4-methylsulfonyloxyphenethenylcarboxamido)phenyl)propanoic acid (62)

According to the procedure described in Example 51, ethyl [2-ethoxy-3-[4-(4-methylsulfonyloxyphenethenylcarboxamido)phenyl]propionate] obtained as described in Example 61 was hydrolyzed with a solution of 372 mg (3.51 mmol) of sodium carbonate in 5 ml of water in 10 ml of methanol at room temperature for 24 hours to give 70 mg (23%) of the title compound as a white solid. M.p.: 164-166°C. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.13 (t, 3H, J = 7.1 Hz), 2.54-2.70 (m, 2H), 2.88-3.10 (m, 4H), 3.12 (s, 3H), 3.22-3.40 (m, 1H), 3.52-3.72 (m, 1H), 3.94 (dd, 1H, J = 4.9 and 7.8 Hz), 7.12-7.50 (m, 8H).

Example 63

2-Ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propanoic acid amino salt (63)

100 mg (1 equivalent, 0.237 mmol) of 2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propanoic acid obtained as described in Example 43 and 41.2 mg (1 equivalent, 0.237 mmol) of L-arginine in 3 ml of anhydrous methanol were stirred at room temperature for 2-3 hours. The solvent was removed on a rotary evaporator and the residue was azeotroped with benzene. The residue was dried under reduced pressure to give the title compound as a free-flowing solid (100%). M.p.: 85-87°C. ¹ H-NMR (DMSO-d ₆ , 200 MHz), δ: 1.02 (t, 3H,J = 6.8 Hz), 1.24 (s, 1H, NH), 1.50-1.90 (m, 6H), 2.55-3.22 (m, 10H), 3.32 (s, 3H), 3.42-3.65 (m, 2H), 6.43 (d,

2H, J = 8.1 Hz), 6.92 (d, 2H, J = 8.1 Hz), 7.24 (d, 2H, J = 8.6 Hz), 7.32 (d, 2H, J = 8.6 Hz), 8.18 (broad s, D ₂ 0 exchangeable)

Example 64

2-Ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propyloxycarbonylamino}phenyl1-propanoic acid arginine salt (64)

The title compound was prepared according to the procedure described in Example 63 from 2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propyloxycarbonylamino}phenyl]propanoic acid obtained as described in Example 44 and L-arginine. M.p.: 180-182°C.

Example 65

2-Ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}phenyl]propanoic acid arginine salt (65)

The title compound was prepared in 100% yield as a free-flowing solid according to the procedure of Example 63 from 95 mg (22 mmol) of 2-ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}-phenylpropanoic acid] obtained as described in Example 46 and 39.3 mg (0.22 mmol) of L-arginine. M.p.: 80-82°C. ¹ H-NMR (DMSO-d ₆ , 200 MHz), δ: 0.99 (t, 3H, J = 6.8 Hz), 1.50-1.90 (m, 7H), 2.55-3.30 (m, 10H), 3.35 (s, 3H), 3.42-3.65 (m, 2H), 5.36 (broad, D ₂ O exchangeable), 6.43 (d, 2H, J = 8.1 Hz), 6.92 (d, 2H, J = 8.1 Hz), 7.10-7.30 aromatic, 3H), 7.30-7.40 (aromatic, 1H), 8.18 (broad s, D ₂ O exchangeable).

Example 66

2-Ethoxy-3-[4-(4-methanesulfonyloxybenzylamino)phenyl]propanoic acid amino salt (66)

The title compound was obtained in 100% yield as a free-flowing solid by the procedure described in Example 63 from 140 mg (0.35 mmol) of 2-ethoxy-3-[4-(4-methanesulfonyloxybenzylamino)phenyl]propanoic acid obtained as described in Example 50 and 68 mg (0.35 mmol) of L-arginine. M.p.: 138-140°C.

¹ H-NMR (DMSO-d ₆ , 200 MHz), δ: 0.98 (t, 3H,J = 6.7 Hz), 1.42-1.82 (m, 4H), 2.553.60 (m, 8H), 3.34 (s, 3H), 4.23 (s, 1H), 4.26 (s, 1H), 6.06 (broad s, 1H), 6.45 (d, 2H,

J = 8 Hz), 6.90 (d, 2H, J = 8.1 Hz), 7.28 (d, 2H, J = 8.6 Hz), 7.45 (d, 2H, J = 8.6 Hz), 8.18 (broad s, D ₂ O exchangeable).

Example 67

2-Ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propanoic acid amino acid salt (67)

The title compound was obtained in 100% yield as a free-flowing solid following the procedure described in Example 63 from 200 mg (0.475 mmol) of 2-ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propanoic acid obtained as described in Example 48 and 83 mg (0.475 mmol) of L-arginine. M.p.: 162-164°C.

Example 68

2-Ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propanoic acid magnesium salt £681 mg (171 µl) of 2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propanoic acid obtained as described in Example 51 in 5 ml of methanol was added 5 mg of magnesium hydroxide and the reaction mixture was refluxed for 24 hours. The methanol was evaporated and the residue was rinsed with toluene to give 50 mg (68%) of the title compound as a white solid. M.p.: 130-134°C. ¹ H-NMR (CD ₃ OD, 200 MHz), δ: 1.10 (t, 3H, J = 6.8 Hz), 2.70-2.96 (m, 4H), 3.18 (s, 3H), 3.22-3.40 (m, 3H), 3.50-3.66 (m, 1H), 3.78-3.91 (m, 1H), 6.58 (d, 2H, J = 8.3 Hz), 7.05 (d, 2H, J = 8.3 Hz), 7.23 (d, 2H, J = 8.8 Hz), 7.32 (d, 2H, J = 8.3 Hz).

Example 69 (S)-2-Ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propanoic acid magnesium salt (69)

To a solution of 170 mg (418 pmol) of (S)-2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propanoic acid obtained as described in Example 52 in 10 ml of methanol was added 12 mg of magnesium hydroxide and the reaction mixture was refluxed for 20 hours. The methanol was evaporated and the residue was rinsed with toluene to give 135 mg of the title compound as a white solid.

Op.: 134-138°C. [a] ²⁵ _D : -26.8°C (c = 0.5, MeOH).

¹ H-NMR (CD ₃ OD, 200 MHz), δ: 1.10 (t, 3H, J = 7.0 Hz), 2.70-2.95 (m, 4H), 3.18 (s, 3H), 3.22-3.40 (m, 3H), 3.50-3.70 (m, 1H), 3.78-3.90 (m, 1H), 6.57 (d, 2H, J = 8.1 Hz), 7.05 (d, 2H, J = 8.3 Hz), 7.23 (d, 2H, J = 8.6 Hz), 7.32 (d, 2H, J = 8.3 Hz).

TS m/z (Cl): 837.2 (M+1).

Example 70 (S)-Ethyl-[2-methoxy-3-[4-{(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino}-phenyl]-propionate] (70)

The title compound was prepared according to the procedure described in Example 37. 892 mg (2.91 mmol) of the compound obtained as described in Example 50 and 500 mg (2.24 mmol) of (S)-ethyl-[2-methoxy-3-(4-aminophenyl)propionate] obtained as described in Example 27 were heated in toluene in the presence of 928 mg (6.72 mmol) of potassium carbonate and 72 mg (0.22 mmol) of tetrabutylammonium bromide for 16 hours. 300 mg (31%) of the title compound were obtained. ¹ H-NMR (CDCl ₃ , 200 MHz), δ: 1.23 (t, 3H, J = 7.2 Hz), 2.91 (d, 2H, J = 6.4 Hz), 3.13 (s, 3H), 3.52 (s, 3H), 3.82-3.98 (m, 2H), 4.03-4.21 (m, 3H), 6.30 (td, 1H, J = 5.4 and 15.8 Hz), 6.54-6.65 (m, 3H), 7.05 (d, 2H, J = 8.3 Hz), 7.22 (d, 2H, J = 8.9 Hz), 7.40 (d, 2H, J = 8.6 Hz). TS m/z (Cl): 434 (M+1).

Example 71 (S)-2-Methoxy-3-[4-((E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino}-phenylpropanoic acid (71)

The title compound was prepared as a pale yellow solid by the procedure described in Example 42. 300 mg (0.69 mmol) of the compound obtained as described in Example 70 was hydrolyzed with 44 mg (1.04 mmol) of lithium hydroxide in 3.5 mL of methanol at room temperature for 5 h. 620 mg (51%) of the title compound were obtained.

Op.: 116-118°C. ¹ H-NMR (DMSO-d ₆ , 200 MHz), δ: 2.75 (t, 2H, J = 7.3 Hz), 3.20 (s, 3H), 3.34 (s, 3H), 3.75-3.92 (m, 3H), 6.40-6.63 (m, 4H), 6.92 (d, 2H, J = 8.3 Hz), 7.28 (d, 2H, J = 8.6 Hz), 7.51 (d, 2H, J = 8.6 Hz). TS m/z (Cl): 406 (M+1).

Example 72 (S)-Ethyl 4-methoxy-3-[4-{3-(3-methanesulfonyloxyphenylpropylamino}phenyl]-propanoate (72)

From 911 mg (2.95 mmol, 1.1 equivalent weight) of 3-(3-methanesulfonyloxypropyl)phenylmethanesulfonate obtained as described in Example 2 and 600 mg (2.69 mmol, 1.0 equivalent weight) of (S)-ethyl-[2-methoxy-3-(4-aminophenyl)propionate] obtained as described in Example 27, 220 mg (35%) of the title compound were obtained as a thick liquid according to the procedure described in Example 29.

¹ H-NMR (CDCI ₃ , 200 MHz), δ: 1.23 (t, 3H, J = 7.2 Hz), 1.92 (quintet, 2H, J = 7.0 Hz), 2.75 (t, 2H, J = 7.0 Hz), 2.90 (d, 2H, J = 6.7 Hz), 3.02-3.20 (m, 5H), 3.34 (s, 3H), 3.89 (t, 1H, J = 6.7 Hz), 4.17 (q, 2H, J = 7.2 Hz), 6.50 (d, 2H, J = 8.3 Hz), 7.02 (d, 2H, J = 8.3 Hz), 7.10-7.40 (aromatic, 4H). IR (neat) cm' ¹ : 3405, 2935, 1739, 1376. TS m/z (Cl): 436 (M+1).

Example 73 (S)-1-Ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}-phenyl-1-propanoic acid (73)

220 mg (1.0 equivalent weight, 0.50 mmol) of ethyl [2-methoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}phenyl]propanoate] obtained as described in Example 72 was hydrolyzed according to the procedure described in Example 42 to give 170 mg (83%) of the desired acid as a viscous liquid after purification by column chromatography.

¹ H-NMR (CDCl3, 400 MHz), δ: 1.94 (quintet, 2H, J = 7.0 Hz), 2.75 (t, 2H, J = 7.0 Hz), 2.92 (dd, 1H, J = 14, 7.3 Hz), 3.03 (dd, 1H, J = 14, 4.3 Hz), 3.10-3.18 (m, 5H), 3.40 (s, 3H), 3.96 (dd, 1H, J = 7.3, 4.3 Hz), 4.40 (broad s, NH, CO ₂ H), 6.53 (d, 2H, J = 8.3 Hz), 7.04 (d, 2H, J = 8.3 Hz), 7.11 -7.35 (aromatic, 4H).

• . · · · · · :

IR (neat) cm' ¹ : 3380, 2924, 1739, 1611, 1522, 1364. TS m/z (Cl): 408 (M+1), 4.30 (M+Na ⁺ ), 8.15 (M ₂ +1)..

Example 74 (S)-2-Methoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}phenyl]-propanoic acid amino salt (74)

The title compound was prepared from 170 mg (1 equivalent, 0.41 mmol) of (S)-2-methoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}phenyl]propanoic acid obtained as described in Example 73 and 73 mg (1 equivalent, 0.41 mmol) of L-arginine. The product was obtained as a free-flowing solid in 100% yield.

Example 75 (S)-Ethyl-r2-ethoxy-3-{4-r(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]phenyl}-propanoate (75)

To a solution of 0.2 g (0.447 mmol) of (S)-ethyl-[2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]phenyl}-propionate] and 0.185 g (1.34 mmol) of potassium carbonate in 3 ml of anhydrous dimethylformamide at room temperature was added dropwise 62 µl (0.537 mmol) of benzoyl chloride, and the reaction mixture was stirred for 20 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, the extract was washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in petroleum ether) to give 0.2 g (81%) of the title compound.

¹ H-NMR (CDCl ₃ , 200 MHz), δ: 7.41-7.05 (m, 11H), 6.94 (d, 2H, J = 8.3 Hz), 6.45-6.34 (m, 2H), 4.65 (d, 2H, J = 5.4 Hz), 4.11 (q, 2H, J = 6.8 Hz), 3.89 (dd, 1H, J = 5.2 and 7.9 Hz), 3.68-3.46 (m, 1H), 3.35-3.19 (m, 1H), 3.13 (s, 3H), 3.02-2.85 (m, 2H), 1.18 (t, 3H, J = 7.2 Hz), 1.06 (t, 3H, J = 7.0 Hz). TS m/z (Cl): 552 (M ⁺ +1.100%).

Example 76 .:λ .tZ. ·.:· -· :

(S)-2-Ethoxy-4-[4-((E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]phenyl}-propanoic acid (76)

To a solution of 0.2 g (0.363 mmol) of (S)-ethyl-[2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]phenyl}-propanoate] obtained as described in Example 75 in 4 ml of methanol was added dropwise a solution of 0.192 g (1.82 mmol) of sodium carbonate in 2 ml of water, and the reaction mixture was stirred at room temperature for 72 hours. The methanol was removed under reduced pressure, the residue was diluted with water and extracted with ethyl acetate. The aqueous phase was cooled to 0°C, adjusted to pH = 2 with 2N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and evaporated. The crude product was chromatographed on silica gel (2% methanol/chloroform) to give 100 mg (53%) of the title compound.

¹ H-NMR (CDCl ₃ , 200 MHz), δ: 7.40-7.04 (m, 11H), 6.96 (d, 2H, J = 8.3 Hz), 6.46-6.37 (m, 2H), 4.66 (d, 2H, J = 5.6 Hz), 4.02-3.92 (m, 1H), 3.60-3.41 (m, 1H), 3.39-3.20 (m, 1H), 3.13 (s, 3H), 3.05-2.80 (m, 2H), 1.06 (t, 3H, J = 7.0 Hz).

Example 77 (S)-2-Ethoxy-3-{4-KE))-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamido1-phenyl}-propanoic acid magnesium salt (77) mg (0.134 mmol) of (S)-2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamido]-phenyl}-propanoic acid obtained as described in Example 76 in 5 ml of methanol was added 4 mg (0.065 mmol) of magnesium hydroxide and the reaction mixture was refluxed overnight. The methanol was evaporated under reduced pressure, the residue was rinsed twice with toluene and triturated in petroleum ether to give 65 mg (89%) of the product as a solid. M.p.: >250°C.

¹ H-NMR (CD3OD, 200 MHz), δ: 7.44 (d, 2H, J = 8.6 Hz), 7.35-7.10 (m, 9H), 7.04 (d, 2H, J = 8.1 Hz), 6.50-6.39 (m, 2H), 4.66 (d, 2H, J = 5.4 Hz), 3.78-3.68 (m, 1H), 3.6099

3.40 (m, 1Η), 3.19 (s, 3H), 3.18-3.02 (m, 1H), 3.00-2.84 (m, 1H), 2.82-2.65 (m, 1H), 0.94 (t, 3H, J = 7.0 Hz). TS m/z (Cl): 1069 (M ⁺ , 24).

Example 78 (S)-Methyl-[2-methoxy-3-{4-[(E)-3-(4-methylsilyloxyphenyl).2-propenyl-(phenyl)carboxamido]phenyl}-propanoate1 (78)

A solution of 0.650 g (1.50 mmol) of (S)-ethyl-[2-methoxy-3-[4-{(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino}-phenyl]propionate obtained as described in Example 70 and 0.621 g (4.50 mmol) of potassium carbonate in 10 ml of anhydrous dimethylformamide was stirred at room temperature for 20 hours, then 0.21 ml (1.8 mmol) of benzoyl chloride was added dropwise, and stirring was continued at room temperature for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, the extract was washed with water, brine, dried over magnesium sulfate and evaporated to dryness in a rotary evaporator. The residue was chromatographed on silica gel (20% ethyl acetate/petroleum ether) to give 372 mg (47%) of the title compound.

¹ H-NMR (CDCl ₃ , 200 MHz), δ: 7.48-7.18 (m, 9H), 7.10 (d, 2H, J = 8.3 Hz), 6.98 (d, 2H, J = 8.3 Hz), 6.52-6.32 (m, 2H), 4.69 (d, 2H, J = 5.4 Hz), 3.91 (t, 1H, J = 6.4 Hz), 3.65 (s, 3H), 3.32 (s, 3H), 3.16 (s, 3H), 3.02-2.88 (m, 2H). TS m/z (Cl): 524 (M ⁺ +1). Example 79 (S)-2-Methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]phenyl]propanoic acid (79)

To a solution of 0.318 g (0.608 mmol) of (S)-methyl-[2-methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]phenyl}-propanoate obtained as described in Example 78 in 5 M methanol was added dropwise a solution of 0.322 g (3.14 mmol) of potassium carbonate in 1 ml of water, and the reaction mixture was stirred at room temperature for 18 hours. The methanol was removed under reduced pressure, the residue was diluted with water and extracted with ethyl acetate. The aqueous phase was cooled to 0°C, adjusted to pH = 2 with 2N hydrochloric acid, and the mixture was concentrated in vacuo.

-acetate. The organic phase was washed with water, brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (40%) ethyl acetate/petroleum ether) to give 220 mg (73%) of the title compound.

¹ H-NMR (CDCl ₃ , 200 MHz), δ: 7.44-7.20 (m, 7H), 7.16 (d, 2H, J = 7.5 Hz), 7.08 (d, 2H, J = 8.3 Hz), 6.96 (d, 2H, J = 8.1 Hz), 6.50-6.28 (m, 2H), 4.66 (d, 2H, J = 5.6 Hz), 3.92 (dd, 1H, J = 4.2 and 7.4 Hz), 3.31 (s, 3H), 3.13 (s, 3H), 3.10-2.85 (m, 2H). TS m/z (Cl): 510 (M ⁺ +1).

Example 80 (S)-2-Methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamidolphenyl}-propanoic acid magnesium salt (80)

To a solution of 0.175 g (0.354 mmol) of (S)-2-methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]phenyl}-propanoic acid obtained as described in Example 79 in 3 ml of methanol was added 10 mg (0.175 mmol) of magnesium hydroxide and the reaction mixture was refluxed for 16 hours. The methanol was removed under reduced pressure, the residue was rinsed twice with toluene and triturated in petroleum ether to give 180 mg (99%) of the title compound. M.p. >250°C. ¹ H-NMR (CD ₃ OD, 200 MHz), δ: 7.40 (d, 2H,J = 8.8 Hz), 7.36-6.96 (m, 11 H), 6.44-6.24 (m, 2H), 4.62 (d, 2H, J = 5.4 Hz), 3.27 (s, 3H), 3.16 (s, 3H), 3.12-2.99 (m, 2H). TS m/z (Cl): 1041 (M ⁺ +1).

Claims (44)

101 * PATENT CLAIMS 1. (I) of general formula - where R ¹ represents hydrogen, halogen, hydroxyl, straight or branched C 1-12 alkyl, straight or branched C 1-12 alkoxy, C 1-12 alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl, or together with the adjacent R ² group forms a bond; R ² represents hydrogen, halogen, straight or branched C 1-12 alkyl, straight or branched C 1-12 alkoxy, C 1-12 alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl or R ² together with R ¹ forms a bond; R ³ represents a hydrogen atom, a substituted or unsubstituted group: a straight or branched, C 1-12 alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, C 1-12 alkanoyl, aroyl, arylalkyl, arylalkanoyl, heterocyclic, heteroaryl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl or arylaminocarbonyl group; R ⁴ represents a hydrogen atom, a straight or branched C 1-12 alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic, heteroaryl or heteroarylalkyl group; Y represents an oxygen atom, a group of the general formula NR ⁷ or N(R ⁷ )O, where R ⁷ represents a hydrogen atom or a substituted or unsubstituted group: a straight or branched, C 1-12 alkyl, aryl, arylalkyl, hydroxyalkyl, alkanoyl, aroyl, arylalkanoyl, heterocyclic, heteroaryl, heteroarylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; R ⁴ and R ⁷ together may form a saturated or unsaturated, 5-6-membered ring structure consisting of carbon atoms and a nitrogen atom, and optionally containing one or more additional heteroatoms, namely oxygen, sulfur or nitrogen atoms. 102 .. R ⁵ represents a hydrogen atom or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aroyl or aralkanoyl group; Ar represents a substituted or unsubstituted divalent group of the following: phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolyl, pyrazolyl, benzothiazolyl, benzoxazolyl or the like; X is -C(=O)-, -C(=S)-, -C(=S)-O-, -C(=O)-O-, -C(=O)-S-, -0-(CH ₂ ) _d -, -NH-(CH ₂ ) _d -, -OC(=O)-, -C(=O)CH ₂ -, -CR ^a =CR ^b -CH ₂ -, -CR ^a =CR ^b -CO- or a group of the general formula, wherein R ^a and R ^b independently represent a hydrogen atom or an alkyl group having 1-6 carbon atoms, d represents an integer of 1-4; or X represents a bond; R ⁶ is a substituted or unsubstituted aryloxycarbonyl, arylalkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl-(Fmoc), fluorenylmethoxycarbonylamino-(N-Fmoc), -OSO2R 8 , -OCONR 8 R 9 , NR 8 COOR 9 , -NR 8 COR 9 , -NR 8 ^{SO2R 9} , -NR ⁸ CONR ⁹ R ¹⁰ , -nr ⁸ csnr 8 r ⁹ , -SO2R ⁸ , -SOR ^{8 , -SR 8} , -SO2NR ^{8 R 9} , -SO ² OR ^{8 ,} -COOR ⁹ , ^{-COR 9 or} _-CONR ^{8 R 9} a group of the general formula, wherein R ⁸ , R ⁹ and R ¹⁰ independently represent a hydrogen atom or a substituted or unsubstituted group: alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; when R ⁸ and R ⁹ are on a nitrogen atom, they may together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms; R ⁶ represents a hydrogen atom when R ¹³ is located at the 3-position of the phenyl ring and does not represent a hydrogen atom; R is hydrogen, halogen, nitro, cyano, amino, halogenated alkyl, hydroxyl or the following groups, substituted or unsubstituted: straight or branched, C1-C12 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryloxy, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc) -OSO ₂ R ⁸ , -OCONR ⁸ R ⁹ , NR ⁸ COOR ⁹ , -NR ⁸ COR ⁹ , -nr ⁸ r ⁹ , -nr ⁸ so2r ⁹ , -nr ⁸ conr ⁹ r ¹⁰ , -nr ⁸ csnr ⁸ r ⁹ , -so2r ⁸ , -sor ⁸ , -sr ⁸ , -SO2NR R , -SO ₂ OR ⁸ , -COOR ⁹ , -COR ⁹ , -CONR ⁸ R ⁹ a group of the general formula, where R ⁸ , R ⁹ and R ¹⁰ independently represent a hydrogen atom or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; when R ⁸ and R ⁹ are on a nitrogen atom, they may together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms; m is an integer from 0 to 6; n is an integer of 0-6 compounds, derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates thereof. 2. A compound of general formula (I) according to claim 1, wherein R ¹ represents a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms, or R ¹ together with R ² forms a bond; R ² represents a hydrogen atom, a straight or branched chain alkyl group having 1 to 6 carbon atoms, or R ² together with R ¹ forms a bond; R represents a hydrogen atom, a straight or branched C1-C12 alkyl, C3-C7 cycloalkyl, aryl or arylalkyl group; R ⁴ represents a hydrogen atom, a straight or branched chain alkyl group having 1-12 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, aryl or arylalkyl; R ⁵ represents a hydrogen atom, a C 1-12 alkyl group or a C 3-7 cycloalkyl group; 104 ....... * R ⁶ is a group of the general formula fluorenylmethoxycarbonyl-(Fmoc), fluorenylmethoxycarbonylamino(N-Fmoc), -OSO2R ⁸ , -OCONR ⁸ R ⁹ , -NR ⁸ COOR ⁹ , -NR ⁸ COR ⁹ , -NR ⁸ SO2R ⁹ ; R represents a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted aryl group; R represents a hydrogen atom, a straight or branched C1-6 alkyl, tert-butyloxycarbonyl or benzyloxycarbonyl group; R ¹³ represents a hydrogen atom or a group of the general formula -OSO ₂ R ⁸ ; X is a group or bond of the formula -C(=O)-, -C(=S)-, -C(O)CH ₂ -, -OC(=O)-, -O(CH ₂ ) _d , -CH=CH-CH ₂ -, -CH=CH-CO-; Y represents an oxygen atom; d is an integer of 1-4; m is 0 or 1; and n is an integer of 0-2. 3. A compound of general formula (I) according to claim 2, wherein R ¹ represents a hydrogen atom or a bond formed together with R ² ; R ² represents a hydrogen atom or a bond formed together with R ¹ ; R ³ represents a hydrogen atom or a straight or branched alkyl group having 1 to 12 carbon atoms; R ⁴ represents a hydrogen atom or a straight or branched alkyl group having 1 to 12 carbon atoms; R ⁵ represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms; R ⁶ is a group of the general formula -OSO 2 R ⁸ or -NR ⁸ SO 2 R ⁹ ; R ⁸ represents a straight or branched C 1-6 alkyl group or a substituted aryl group, wherein the substituent is a straight or branched C 1-6 alkyl group; 105 “ R ⁹ is a straight or branched C 1-6 alkyl, tert-butyloxycarbonyl or benzyloxycarbonyl group; R ¹³ represents a hydrogen atom or a group of the general formula -OSO ₂ R ⁸ ; X is a group or bond of the formula -C(=O)-, -OC(=O)-, -O(CH ₂ ) _d , -CH=CH-CH ₂ -, -CH=CH-CO-; Y represents an oxygen atom. 4. A compound according to claims 1-3, selected from the following: ethyl-[2-methoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propyloxycarbonylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(4-(toluene-4-sulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl [2-isopropoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionate], ethyl [2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino}-phenyl]-propionate], ethyl [2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]-phenyl}-propionate], methyl [2-ethoxy-3-[4-(4-methanesulfonyloxybenzylamino)-phenyl]-propionate], 2-Methoxy-3-[4-{3-(4-methanesulfonyloxy-phenyl)-propyl-amino}-phenyl]-propionic acid, 2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propionic acid, 2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propyloxycarbonylamino}phenyl]propionic acid, 2-ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}phenyl]propionic acid, 2-ethoxy-3-[4-{3-(4-(toluene-4-sulfonyloxy)phenyl)propylamino}phenyl]propionate, 106 2-ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propionic acid, 2-isopropoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propionic acid, 2-ethoxy-3-[4-(4-methanesulfonyloxy-benzylamino)-phenyl]-propionic acid, 2-ethoxy-3-[4-(4-methylsulfonyl-oxy-phenethyl-amino)-phenyl]-propionic acid, 2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyl-oxy-phenyl)-propenyl-amino)-phenyl]-propionic acid, ethyl [2-ethoxy-3-[4-(4-methylsulfonyloxy-benzylcarboxamido)-phenyl]-propionate], 2-θίοχί-3-[4-(4^θίΐΙ-8ζυΙίοηϊΙ-οχΐ^θηζίΙ^3ώοχ3ΐΐ^ο)-ίθηΐΙ]-ρΓΌρίοη53ν, ethyl [2-ethoxy-3-[4-(3-tert-butoxy-4-methylsulfonamidophenyl)propylamino}phenylpropionate], 2-Ethoxy-3-[4-{3-(4-tert-butoxy-4-methylsulfonamidophenyl)propylamino}phenyl]propionic acid, ethyl [2-ethoxy-3-{4-[(E)-2-(4-methylsulfonyloxyphenyl)-1-ethenylcarboxamido]phenyl}propionate], 2-Ethoxy-3-{4-[(E)-2-(4-methylsulfonyloxyphenyl)-1-ethenylcarboxamido]phenyl}-propionic acid, ethyl-[2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylcarboxamido)phenyl]-propionate], 2-Ethoxy-3-[4-(4-methylsulfonyloxyphenethenylcarboxamido)phenyl]-propanoic acid, ethyl-[2-methoxy-3-[4-{(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino}-phenyl]-propionate], 2-methoxy-3-[4-{(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino}-phenyl]-propionic acid, ethyl [2-methoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propanoate], 2-Methoxy-3-[4-{3-(3-methanesulfonyloxy-phenyl)-propyl-amino}-phenyl]-propionic acid, 107 ethyl [2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]phenyl]propanoate], 2-Ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamidophenyl]-propionic acid, methyl-[2-methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamido]-phenyl}-propanoate], 2-Methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]enyl}-propanoic acid or its salts in enantiomeric form or as racemate. 5. The compounds of claim 1, wherein the pharmaceutically acceptable salt is selected from the following: Li-, Na-, K-, Ca-, Mg-, Fe-, Cu-, Zη-, Al-, Mn-salts' salts formed with the following organic bases: Ν,Ν'-diacetylethylenediamine, betaine, caffeine 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, theobromine, valinol, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamantylamine, diethanolamine, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, Ν,Ν'-dibenzylethylenediamine, N-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine and the like; alkylphenylamine, glycinol, phenylglycinol; and the like; glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; salts of unnatural amino acids, D-isomers or substituted amino acids; salts of acidic amino acids such as aspartic acid, glutamic acid; salts of guanidine or guanidine substituted with nitro-, amino-, alkyl-, alkenyl-, alkynyl-groups; salts of ammonium and substituted ammonium; sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides (HCl, HBr, Hl), acetates, tartrates, maleates, citrates, succinates, palmoates, 108 methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates. 6. A process for the preparation of a compound of formula (I) - wherein all symbols are as defined in claim 1 -, its derivatives, analogs, tautomeric forms, stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates thereof, which comprises: (a) reacting a compound of formula (IIIa) - wherein R ⁵ , R ⁶ , R ¹³ , X, _m and Ar are as defined in claim 1 - with a compound of formula (IIIb) - wherein Y is as defined in claim 1 except for NH; R ¹¹ is a straight or branched alkyl group having 1 to 6 carbon atoms, and all other symbols are as defined in claim 1 - to obtain a compound of claim (I), wherein Y is as defined above except for NH, and all symbols are as defined above; or (b) reacting a compound of formula ⁽ Ilid) wherein ^R6 , ^R13 are as defined above except for the group of formula ^NR8R9 , Y is as defined in claim 1 except for the group of formula NH, and all other symbols are as defined above with a compound of formula (Ilile) wherein ^R3 is as defined in claim 1 except for hydrogen, and ^L1 is a leaving group to give a compound of formula (I) wherein Y is as defined above except for the group of formula NH, and all other symbols are as defined above; or (c) reacting a compound of formula (IIIa) wherein all symbols are as defined above with a compound of formula (IIIe) wherein ^R2 is hydrogen; Y is as defined above except for NH, and all other symbols are as defined above, to give (I) to obtain a compound of general formula 109, wherein Y is as defined above, except for the group of formula NH, and all other symbols are as defined above; (d) reacting a compound of formula (IIIg) wherein R ⁶ , R ¹³ , X and n are as defined in claim 1 and L ¹ is a leaving group with a compound of formula (IIIf) wherein R ¹ and R ² together form a bond and all other symbols are as defined above to obtain a compound of formula (I); or (e) reacting a compound of formula (IIIh) wherein R ⁶ , R ¹³ , X and n are as defined in claim 1 with a compound of formula (IIIf) wherein R ¹ and R ² together form a bond and all other symbols are as defined above to obtain a compound of formula (I); or (f) reacting the compound of formula (IIIi) wherein all symbols are as defined above with the compound of formula (IIIj) wherein Y is oxygen; ^R3 = ^R4 and are as defined above, except for hydrogen, to give the compound of formula (I) wherein Y is oxygen and all other symbols are as defined above; or (9) reducing ^the compound of formula (IVa) corresponding to a compound of formula (I) wherein R ¹ and R ² together form a bond, Y is oxygen, and all other symbols are as defined above to obtain the compound of formula (I) wherein R ¹ and R ² are each hydrogen, and all other symbols are as defined above; or (h) a compound of formula (IVb) - wherein R ⁴ is as defined above except for hydrogen, L ¹ is a leaving group, and all other symbols are as defined above. 110 se the compound defined above - is reacted with the compound of general formula (IVc) - wherein R ³ is as defined above, excluding hydrogen - to obtain the compound of general formula (I); or (i) reacting the compound of formula (IIIg) wherein each symbol is as defined above with the compound of formula (IIIf) wherein each symbol is as defined above to give the compound of formula (I) wherein each symbol is as defined above; or (j) coupling the compound of formula (IIIh) wherein each symbol is as defined above with the compound of formula (IIIf) wherein each symbol is as defined above to give the compound of formula (I) wherein each symbol is as defined above; or (k) reacting a compound of formula (Ilid) wherein all symbols are as defined above with a compound of formula (Ile) wherein ^R3 is as defined above except for hydrogen and ^L1 is a leaving group to give a compound of formula (I) wherein all symbols are as defined above; or (0) reacting a compound of formula (IIIa) wherein all symbols are as defined above with a compound of formula (IIIe) wherein ^R2 is hydrogen, Y is as defined above except for NH, and all other symbols are as defined above to give a compound of formula (I) wherein ^R2 is hydrogen, Y is as defined above except for NH, and all other symbols are as defined above; or (m) converting the compound of formula (IVd) wherein all symbols are as defined above into a compound of formula (I) wherein Y is oxygen and all other symbols are as defined above in the presence of an acid or base; or (n) reacting the compound of formula (IVe) - wherein R ⁴ is as defined above except for hydrogen and all other symbols are as defined above - with the compound of formula (IVc) - wherein R ³ is as defined above except for hydrogen - to obtain the compound of formula (I) - wherein R ³ and R ⁴ are as defined above except for hydrogen and all other symbols are as defined above; or (o) The compound of formula (IVg) - where G ² is a group of the formula NH2 or -CHO, and all symbols are as defined above - is reacted with the compound of formula (IVf) - where G ¹ is a group of the formula NH2 when G ² is a group of the formula -CHO, or G ¹ is a group of the formula -CHO when G ² is a group of the formula _NH2 , q is 0-6, and all other symbols are as defined above - to obtain the compound of formula (I), where R ⁵ is a hydrogen atom and all other symbols are as defined above. 7. (Illa) general formula - where R ⁵ represents a hydrogen atom, an alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl, aryl or aryl-alkyl group, each of which groups may be substituted or unsubstituted; n and m represent an integer of 0-6; Ar represents a substituted or unsubstituted divalent group of the following: phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl 112 azaindolinyl, pyrazolyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like; ; the substituent of the Ar group may be a straight or branched, optionally halogenated C1-6 alkyl, optionally halogenated C1-3 alkoxy, halogen, acyl, amino, acylamino, thio, carboxylic acid or sulfonic acid group or a derivative thereof; X is a group of the formula C=O, C=S, -C(O)CH ₂ -, -CH=CH-CH ₂ , -CH=CH-CO- or X is a bond; R ⁶ is a group of the general formula aryloxycarbonyl, arylalkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl-(Fmoc), fluorenylmethoxycarbonylamino-(N-Fmoc), -OSO2R ⁸ , OCONR 8 R ⁹ *nr ⁵ coor' ^j -nr ⁸ cor ⁹ , -nr ⁸ so2r 9 , nr'conr'r 10 , -nr ⁸ csnr 0 r 9 , -so2r", -SOR ⁸ , -SR ⁸ , -SO2NR ⁸ R ⁹ , -SO ^{2 OR b} , -COOR ⁹ , -COR ⁹ or -CONR'R ^{9 ,} each of ^which may be substituted or _{unsubstituted} ^and R ⁸ , R ⁹ and R ¹⁰ are independently hydrogen, alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl, each of which may be substituted or unsubstituted; where R ⁸ and R ⁹ are located on a nitrogen atom, they may together form a 5- or 6-membered ring structure consisting of carbon atoms and one or more heteroatoms, which may be oxygen, sulfur or nitrogen atoms; or R ⁶ is hydrogen when R ¹³ is located at the 3-position of the phenyl ring and is not hydrogen; R ¹³ is hydrogen, halogen, nitro, cyano, amino, halogenated alkyl, hydroxyl or substituted or unsubstituted alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryloxy, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc).fluorenylmethoxycarbonylamino (N-Fmoc), -OSO ₂ R ⁸ , -OCONR ⁸ R ⁹ , NR ⁸ COOR ⁹ , -NR ⁸ COR ⁹ 113 -nr ⁸ r ⁹ , -nr ⁸ so2r ⁹ , -NR ⁸ CONR ⁹ R ¹⁰ , -NR ⁸ CSNR ⁸ R ⁹ , -SO2R ⁸ , -sor ⁸ , -SR ⁸ , -SO2NR ⁸ R ⁹ , -SO2OR ⁸ , -COOR ⁹ , -COR ⁹ , -CONR ⁸ R ⁹ , where R ⁸ , R ⁹ and R ¹⁰ independently represent a hydrogen atom or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group' when R ⁸ and R ⁹ are on a nitrogen atom, they can together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms intermediates, derivatives, analogues, tautomeric forms, stereoisomers, salts, solvates. 8. A process for the preparation of a compound of general formula (IIIa) according to claim 7, its derivatives, analogues, tautomeric forms, stereoisomers thereof, which comprises (a) (i) reacting a compound of general formula (IIIa) - where X is a group or bond of the formula -C(O)CH ₂ -, -CH=CH-CH ₂ -, R ⁶ and R ¹³ are as defined in claim 6 - with a compound of general formula (III?) - where R ¹² is a hydrogen atom or a C 1-6 alkyl group, m is as defined above - to obtain a compound of general formula (IIIm) - where all symbols are as defined above; (ii) and the compound of formula (IIIm) is converted in the presence of an acid or base to a compound of formula (IIIa), wherein ^R5 is hydrogen; X is a group or bond of the formula -C(O) _CH2- , -CH=CH- _CH2- ; m is 0; Ar is phenyl, and all other symbols are as defined above; or (b) reacting a compound of formula (IIIg) wherein each symbol is as defined above with a compound of formula (IIIn) wherein R ¹² is hydrogen or alkyl, m is an integer of 0-6, and R ⁵ is as defined above to give a compound of formula (IIIa) wherein R ^{5 is} 114 represents a hydrogen atom or an alkyl group; m represents 0 or 1, and all other symbols have the meanings defined above. 9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-5, together with a pharmaceutically acceptable carrier, diluent, excipient or solvent. 10. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1-5 and an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, a hypoglycemic agent, an insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and γ agonist or a mixture thereof, accompanied by a pharmaceutically acceptable carrier, diluent, excipient or solvent. 11. A pharmaceutical composition according to claim 9 or 10 in the form of a tablet, capsule, powder, syrup, solution or suspension. 12. A compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prevention of diabetes caused by insulin resistance or impaired glucose tolerance. 13. A compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claims 9 or 10 for the treatment of diabetes or a complication of diabetes caused by insulin resistance or impaired glucose tolerance, wherein the complication of diabetes is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary heart disease, cardiovascular diseases; kidney diseases, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy; retinopathy, endothelial cell activation-related 115 diseases, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, for the treatment and/or prevention of cancer or for use as an aldose reductase inhibitor or anti-inflammatory. 14. A compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prevention of diabetes caused by insulin resistance or impaired glucose tolerance, for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance. 15. A compound of general formula (I) according to any one of claims 1-5 for the treatment and/or prevention of diabetes caused by insulin resistance or impaired glucose tolerance, or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prevention of disorders associated with syndrome X. 16. The compound or pharmaceutical composition of claim 15, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease, or a cardiovascular disorder. 17. A compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prevention of diabetes caused by insulin resistance or impaired glucose tolerance, for reducing total cholesterol, body weight, blood plasma glucose, insulin, _HbA1C , triglyceride, LDL, VLDL or free fatty acid levels or for increasing HDL levels. 18. A compound of general formula (I) according to any one of claims 1-5, with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent <·*·** · · · · *1 * ’· ····· 116 .:.. .·· . ·..· -.-· : a pharmaceutical composition for the treatment and/or prevention of diabetes caused by insulin resistance or impaired glucose tolerance, comprising in combination with an active ingredient, an active ingredient for the treatment of lipoprotein disorders, insulin, biguanide, sulfonylurea, thiazolidinedione or dual PPAR-α and γ agonist or mixtures thereof, for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance, 19. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1-5 in combination with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, insulin, biguanide, sulfonylurea, thiazolidinedione or dual PPAR-α and γ agonist or mixtures thereof for the treatment of diabetes or a complication of diabetes caused by insulin resistance or impaired glucose tolerance, wherein the complication of diabetes is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary heart disease, cardiovascular diseases; kidney diseases, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy; retinopathy, diseases associated with endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, for the treatment and/or prevention of cancer or for use as an aldose reductase inhibitor or anti-inflammatory agent. 20. A method for treating obesity by combining the compound of general formula (I) according to any one of claims 1-5 with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, 117 A pharmaceutical composition comprising in combination with an active ingredient, an active ingredient for the treatment of a lipoprotein disorder, insulin, a biguanide, a sulfonylurea, a thiazolidinedione or a dual PPAR-α and γ agonist or mixtures thereof, for the treatment and/or prevention of disorders associated with syndrome X. 21. The pharmaceutical composition of claim 20, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary heart disease, or a cardiovascular disorder. 22. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1-5 in combination with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, insulin, biguanide, sulfonylurea, thiazolidinedione or dual PPAR-α and γ agonist or mixtures thereof for reducing total cholesterol, body weight, blood plasma glucose, insulin, HbAic, triglyceride, LDL, VLDL or free fatty acid levels or increasing HDL levels. 23. Use of a compound of general formula (I) according to any one of claims 1-5 or a composition according to claim 9 or 10 for the treatment and/or prevention of diabetes caused by insulin resistance or impaired glucose tolerance. 24. Use of a compound of formula (I) according to any one of claims 1 to 5 or a composition according to claim 9 or 10 for the treatment of diabetes or a complication of diabetes caused by insulin resistance or impaired glucose tolerance, wherein the complication of diabetes is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary heart disease, cardiovascular diseases; kidney diseases, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive 118 nephrosclerosis, nephropathy, retinopathy, endothelial cell activation-related diseases, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, for the treatment and/or prevention of cancer or for use as an aldose reductase inhibitor or anti-inflammatory. 25. Use of a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance. 26. Use of a compound of formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prevention of disorders associated with syndrome X, which comprises the use of a PPAR-α and/or PPAR-γ agonist. 27. The use of claim 26, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease, or cardiovascular disorder. 28. Use of a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 for reducing total cholesterol, body weight, blood plasma glucose, insulin, HbA _1c , triglyceride, LDL, VLDL or free fatty acid levels or increasing HDL levels. 29. A compound of formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10, in combination with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of a lipoprotein disorder, a hypoglycemic agent. 119 * combined use with sel, insulin, biguanide, sulfonylurea, thiazolidinedione, dual PPAR-α and β agonists, or use with the above within a period of time resulting in a synergistic and/or additive effect, for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, impaired glucose tolerance, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance. 30. Use of a compound of formula (I) according to any one of claims 1 to 5 or a composition according to claim 9 or 10 for the treatment of diabetes or a complication of diabetes caused by insulin resistance or impaired glucose tolerance, wherein the complication of diabetes is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary heart disease, cardiovascular diseases; kidney diseases, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy; retinopathy, endothelial cell activation-related diseases, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, for the treatment and/or prevention of cancer or for use as an aldose reductase inhibitor or anti-inflammatory agent. 31. The combined use of the compound of general formula (I) according to any one of claims 1-5 or the pharmaceutical composition according to claim 9 or 10 with an HMG CoA reductase inhibitor, an agent inhibiting cholesterol absorption, an anti-obesity agent, an agent for treating lipoprotein disorders, a hypoglycemic agent, an insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and β agonist, or the use thereof within a period of time resulting in a synergistic and/or additive effect with the above-mentioned X 120 syndrome-related disorders, comprising administering a PPAR-α and/or PPAR-γ agonist to a patient in need of treatment. 32. The use of claim 31, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease, or cardiovascular disorder. 33. The combined use of a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and γ agonist, or the use thereof within a period of time resulting in a synergistic and/or additive effect, for reducing total cholesterol, body weight, blood plasma glucose, insulin, HbAic, triglyceride, LDL, VLDL or free fatty acid levels or increasing HDL levels. M/S 12. The authorized person: ·* · · · · · · ···*·*·· *· «· · j IP04 0 2 55 0 I PATENT CLAIMS ♦ ’ (original) 1. (I) of general formula - where R ¹ represents hydrogen, halogen, hydroxyl, straight or branched C 1-12 alkyl, straight or branched C 1-12 alkoxy, C 1-12 alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl or forms a bond with the adjacent R ² group; R ² represents hydrogen, halogen, straight or branched C 1-12 alkyl, straight or branched C 1-12 alkoxy, C 1-12 alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl or R ² together with R ¹ forms a bond; R ³ represents a hydrogen atom, a substituted or unsubstituted group: a straight or branched, C 1-12 alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, C 1-12 alkanoyl, aroyl, arylalkyl, arylalkanoyl, heterocyclic, heteroaryl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl or arylaminocarbonyl group; R ⁴ represents a hydrogen atom, a straight or branched alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic, heteroaryl or heteroarylalkyl group having 1 to 12 carbon atoms; Y represents an oxygen atom, a group of the general formula NR ⁷ or N(R ⁷ )O, where R ⁷ represents a hydrogen atom or a substituted or unsubstituted group: a straight or branched, C 1-12 alkyl, aryl, arylalkyl, hydroxyalkyl, alkanoyl, aroyl, arylalkanoyl, heterocyclic, heteroaryl, heteroarylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; 123 .......... ' ' R ⁴ and R ⁷ together may form a saturated or unsaturated 5-6 membered ring structure consisting of carbon atoms and nitrogen atoms, and optionally containing one or more additional heteroatoms, namely oxygen, sulfur or nitrogen atoms; R ⁵ represents a hydrogen atom or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aroyl or aralkanoyl group; Ar represents a substituted or unsubstituted divalent group of the following: phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolyl, pyrazolyl, benzothiazolyl, benzoxazolyl or the like; X is -C(=O)-, -C(=S)-, -C(=S)-O-, -C(=O)-O-, -C(=O)-S-, -O-(CH ₂ ) _d -NH-(CH ₂ ) _d -, -OC(=O)-, -C(=O)CH ₂ -, -CR ^a =CR ^b -CH ₂ -, -CR ^a =CR ^b -CO- or a group of the general formula, wherein R ^a and R ^b independently represent a hydrogen atom or an alkyl group having 1-6 carbon atoms, d represents an integer of 1-4; or X represents a bond; R ⁶ is a substituted or unsubstituted group: aryloxycarbonyl, arylalkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl-(Fmoc), fluorenylmethoxycarbonylamino-(N-Fmoc), -OSO2R 8 , -OCONR 8 R 9 , NR 8 COOR 9 , -NR 8 COR 9 , -NR 8 SO2R ⁹ , -NR ⁸ CONR ⁹ R ¹⁰ , -NR ⁸ CSNR 8 R ⁹ , -SO2R ⁸ , -SOR ^{8 , -SR 8} , -SO2NR ⁸ R ^{9 ,} -SO ^{2 OR 8 , -COOR 9 , -COR 9 or} -CONR ^{8 R 9} _general a group of formula wherein R ⁸ , R ⁹ and R ¹⁰ are independently hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; when R ⁸ and R ⁹ are on a nitrogen atom, they may together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms; R ⁶ is hydrogen when R ¹³ is at the 3-position of the phenyl ring and is not hydrogen; 13. ' R is hydrogen, halogen, nitro, cyano, amino, halogenated alkylhydroxyl or substituted or unsubstituted alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryloxy, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO ₂ R ⁸ , -OCONR ⁸ R ⁹ , NR ⁸ COOR ⁹ , a group of the general formula -NR ⁸ COR ⁹ , -NR ⁸ R ⁹ , -NR ⁸ SO ₂ R ⁹ , -NR ⁸ CONR ⁹ R ¹⁰ , -NR ⁸ CSNR ⁸ R ⁹ , -SO2R ⁸ , -SOR ⁸ , -SR ⁸ , -SO2NR ⁸ R ⁹ , -SO ₂ OR ⁸ , -COOR ⁹ , -COR ⁹ , -CONR ⁸ R ⁹ , where R ⁸ , R ⁹ and R ¹⁰ independently represent a hydrogen atom or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; when R ⁸ and R ⁹ are on a nitrogen atom, they can together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms; m is an integer from 0 to 6; n is an integer of 0-6. Compounds, derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates thereof. 2. A compound of general formula (I) according to claim 1, wherein R ¹ represents a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms, or R ¹ together with R ² forms a bond; R ² represents a hydrogen atom, a straight or branched chain alkyl group having 1 to 6 carbon atoms, or R ² together with R ¹ forms a bond; R ³ represents a hydrogen atom, a straight or branched C 1-12 alkyl, C 3-7 cycloalkyl, aryl or arylalkyl group; R ⁴ represents a hydrogen atom, a straight or branched chain alkyl group having 1-12 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, aryl or arylalkyl; R represents a hydrogen atom, a C1-C12 alkyl group or a C3-C7 cycloalkyl group; R is a group of the general formula fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO ₂ R', -OCONR ^a R ⁹ , -NR'COOR ⁹ , -NR'coR ⁹ , -NR ^b SO ₂ R ⁹ ; R represents a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted aryl group; R ⁹ represents a hydrogen atom, a straight or branched C 1-6 alkyl group, tert-butyloxycarbonyl or benzyloxycarbonyl group; R ¹³ represents a hydrogen atom or a group of the general formula -OSO ₂ R ⁸ ; X is a group or bond of the formula -C(=O)-, -C(=S)-, -C(O)CH ₂ -, -OC(=O)-, -O(CH ₂ ) _a , -CH=CH-CH ₂ -, -CH=CH-CO-; Y represents an oxygen atom; d is an integer of 1-4; m is 0 or 1; and n is an integer of 0-2. 3. A compound of general formula (I) according to claim 2, wherein R ¹ represents a hydrogen atom or a bond formed together with R ² ; R represents a hydrogen atom or a bond formed together with R ¹ ; R ³ represents a hydrogen atom or a straight or branched alkyl group having 1 to 12 carbon atoms; R represents a hydrogen atom or a straight or branched alkyl group having 1 to 12 carbon atoms; R ⁵ represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms; R ⁶ is a group of the general formula -OSO 2 R ⁸ or -NR ⁸ SO 2 R ⁹ ; 126 ....... “ * R ⁸ represents a straight or branched C 1-6 alkyl group or a substituted aryl group, wherein the substituent is a straight or branched C 1-6 alkyl group; R ⁹ is a straight or branched C 1-6 alkyl, tert-butyloxycarbonyl or benzyloxycarbonyl group; R ¹³ represents a hydrogen atom or a group of the general formula -OSO ₂ R ⁸ ; X is a group or bond of the formula -C(=O)-, -OC(=O)-, -O(CH ₂ ) _d , -CH=CH-CH ₂ -, -CH=CH-CO-; Y represents an oxygen atom. 4. A compound according to claim 1-3, selected from the following: ethyl-[2-methoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propyloxycarbonylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-{3-(4-(toluene-4-sulfonyloxy)-phenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionate], onate], ethyl-[2-isopropoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino}-phenyl]-propionate], ethyl-[2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]-phenyl}-propionate], methyl-[2-ethoxy-3-[4-(4-methanesulfonyloxybenzylamino)-phenyl]-propionate], 2-methoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionic acid, 2-ethoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)propylamino}phenyl]propionic acid, 4 · 4· · « ··♦·*«♦· «·<*«« 4· , · · · · · b f ·· 127 - * · 2-ethoxy-3-[4-{3-(4-methanesulfonyloxy-phenyl)-propyl-oxy-carbonyl-amino}-phenyl]-propionic acid, 2-ethoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionic acid, 2-ethoxy-3-[4-{3-(4-(toluene-4-sulfonyloxy)-phenyl)-propylamino}-phenyl]-propionate, 2-ethoxy-3-[3-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionic acid, 2-isopropoxy-3-[4-{3-(4-methanesulfonyloxyphenyl)-propylamino}-phenyl]-propionic acid, 2-Ethoxy-3-[4-(4-methanesulfonyloxybenzylamino)phenyl]propionic acid, 2-Ethoxy-3-[4-(4-methylsulfonyloxyphenethylamino)phenyl]propionic acid, 2-Ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)propenylamino}phenyl]propionic acid, ethyl [2-ethoxy-3-[4-(4-methylsulfonyloxybenzylcarboxamido)phenyl]propionate], 2-Ethoxy-3-[4-(4-methylsulfonyloxybenzylcarboxamido)phenyl]propionic acid, ethyl [2-ethoxy-3-[4-(3-tert-butoxy-4-methylsulfonamidophenyl)propylamino}phenylpropionate], 2-Ethoxy-3-[4-{3-(4-tert-butoxy-4-methylsulfonamidophenyl)propylamino}phenyl]propionic acid, ethyl [2-ethoxy-3-{4-[(E)-2-(4-methylsulfonyloxyphenyl)-1-ethenylcarboxamido]phenyl}propionate], 2-Ethoxy-3-{4-[(E)-2-(4-methylsulfonyloxyphenyl)-1-ethenylcarboxamido]phenyl}-propionic acid, ethyl-[2-ethoxy-3-[4-(4-methylsulfonyloxyphenethylcarboxamido)phenyl]-propionate], 2-Ethoxy-3-[4-(4-methylsulfonyloxyphenethenylcarboxamido)phenyl]-propanoic acid, ethyl-[2-methoxy-3-[4-{(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino}-phenyl]-propionate], 2-Methoxy-3-[4-{(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino}-phenyl]-propionic acid, ethyl [2-methoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}phenyl]propanoate], 2-methoxy-3-[4-{3-(3-methanesulfonyloxyphenyl)propylamino}-phenyl]-propionic acid, ethyl [2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamido]-phenyl}-propanoate], 2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamido]-phenyl}-propionic acid, methyl [2-methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)-carboxamido]-phenyl}-propanoate], 2-Methoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenyl-(phenyl)carboxamido]enyl}-propanoic acid or its salts in enantiomeric form or as a racemate. 5. Compounds according to claim 1, wherein the pharmaceutically acceptable salt is selected from the following: Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn salts; salts with the following organic bases: Ν,Ν'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, theobromine, valinol, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamantylamine, diethanolamine, meglumine, ethylenediamine, Ν,Ν'-diphenylethylenediamine, Ν,Ν'-dibenzylethylenediamine, N-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine and the like; chiral bases such as alkylphenylamine, glycinol, phenylglycinol; glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids; D-isomers or salts of substituted amino acids; salts of acidic amino acids such as aspartic acid, glutamic acid; guanidine or nitro-, salts of guanidine substituted with amino, alkyl, alkenyl, alkynyl groups; salts of ammonium and substituted ammonium; sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides (HCl, HBr, Hl), acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates. 6. A process for the preparation of a compound of formula (I) - wherein R ⁵ , R ⁶ , R ¹³ , X, _m and Ar are as defined in claim 1 -, derivatives, analogues, tautomeric forms, stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates thereof, which comprises: (a) reacting a compound of formula (IIIa) - wherein all symbols are as defined in claim 1 - with a compound of formula (IIIb) - wherein Y is as defined in claim 1 except for the NH group; R ¹¹ is a straight or branched alkyl group having 1-6 carbon atoms, and all other symbols are as defined in claim 1 - to obtain a compound of claim (I), wherein Y is as defined above except for the NH group, and all symbols are as defined above; or (b) reacting a compound of formula ⁽ Ilid) wherein ^R6 , ^R13 are as defined above except for the group of formula ^NR8R9 , Y is as defined in claim 1 except for the group of formula NH, and all other symbols are as defined above with a compound of formula (Ilile) wherein ^R3 is as defined in claim 1 except for hydrogen, and ^L1 is a leaving group to give a compound of formula (I) wherein Y is as defined above except for the group of formula NH, and all other symbols are as defined above; or (c) reacting a compound of formula (IIIa) wherein all symbols are as defined above with a compound of formula (IIIe) wherein ^R2 is hydrogen; Y is as defined above except for NH and all other symbols are as defined above to give a compound of formula (I) wherein Y is as defined above except for NH and all other symbols are as defined above; (d) reacting a compound of formula (IIIg) wherein R ⁶ , R ¹³ , X and n are as defined in claim 1 and L ¹ is a leaving group with a compound of formula (IIIf) wherein R ¹ and R ² together form a bond and all other symbols are as defined above to obtain a compound of formula (I); or (e) reacting a compound of formula (IIIh) wherein R ⁶ , R ¹³ , X and n are as defined in claim 1 with a compound of formula (IIIf) wherein R ¹ and R ² together form a bond and all other symbols are as defined above to obtain a compound of formula (I); or (f) reacting the compound of formula (Ilii) - where all symbols are as defined above - with the compound of formula (IIIj) - where Y is oxygen; R3 ^{= R4} and their meanings are as defined above, except for hydrogen - to obtain the compound of formula (I) - where Y is oxygen and all other symbols are as defined above; or (g) reducing a compound of formula (IVa) corresponding to a compound of formula (I) wherein R and R together form a bond, Y represents an oxygen atom, and all other symbols are as defined above, to give (I) 131 : to obtain a compound of the general formula wherein R ¹ and R ² each represent a hydrogen atom and all other symbols are as defined above; or (h) reacting a compound of formula (IVb) wherein R ⁴ is as defined above except for hydrogen, L ¹ is a leaving group, and all other symbols are as defined above with a compound of formula (IVc) wherein R ³ is as defined above except for hydrogen to give a compound of formula (I); or (i) reacting a compound of formula (IIIg) wherein each symbol is as defined above with a compound of formula (IIIf) wherein each symbol is as defined above to give a compound of formula (I) wherein each symbol is as defined above; or (j) coupling the compound of formula (IIlh) wherein each symbol is as defined above with the compound of formula (IIIf) wherein each symbol is as defined above to give the compound of formula (I) wherein each symbol is as defined above; or (k) reacting a compound of formula (Ilid) wherein all symbols are as defined above with a compound of formula (Ile) wherein ^R3 is as defined above except for hydrogen and ^L1 is a leaving group to give a compound of formula (I) wherein all symbols are as defined above; or (0) a compound of the general formula (IIIa) - where all symbols have the meanings defined above - is a compound of the general formula (IIIa) - where R ² is a hydrogen atom, Y 132 is as defined above except for the group of formula NH, and all other symbols are as defined above - is reacted with a compound of formula (I) to obtain a compound of formula (I), wherein R ² is hydrogen, Y is as defined above except for the group of formula NH, and all other symbols are as defined above; or (m) converting the compound of formula (IVd) wherein all symbols are as defined above into a compound of formula (I) wherein Y is oxygen and all other symbols are as defined above in the presence of an acid or base; or (n) reacting the compound of formula (IVe) - wherein R ⁴ is as defined above except for hydrogen and all other symbols are as defined above - with the compound of formula (IVc) - wherein R ³ is as defined above except for hydrogen - to obtain the compound of formula (I) - wherein R ³ and R ⁴ are as defined above except for hydrogen and all other symbols are as defined above; or (o) The compound of formula (IVg) - where G ² is a group of formula NH2 or -CHO, and all symbols are as defined above - is reacted with the compound of formula (IVf) - where G ¹ is a group of formula NH2 when G ² is a group of formula -CHO, or G ¹ is a group of formula -CHO when G ² is a group of formula _NH2 , q is 0-6, and all other symbols are as defined above - to obtain the compound of formula (I), where R ⁵ is a hydrogen atom and all other symbols are as defined above. 7. (Illa) general formula - where 133 R represents a hydrogen atom, an alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl, aryl or aryl-alkyl group, each of which groups may be substituted or unsubstituted; n and m represent an integer of 0-6; Ar represents a substituted or unsubstituted divalent group of the following: phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl-azaindolinyl, pyrazolyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like; ; the substituent of the Ar group may be a straight or branched, optionally halogenated C1-6 alkyl, optionally halogenated, C1-3 alkoxy, halogen, acyl, amino, acylamino, thio, carboxylic acid or sulfonic acid group or a derivative thereof; X represents a group of the formula C=O, C=S, -C(O)CH ₂ -, -CH=CH-CH ₂ , -CH=CH-CO- or X represents a bond; R ⁶ is a group of the general formula -OSO2R 8 , OCONR 8 R 9 -NR 8 COOR 9 , -NR 8 COR 9 , -NR 8 SO2R 9 , NR ⁸ CONR 9 R 10 , -NR 8 CSNR 8 R ⁹ , -SO2R ⁸ -SOR ⁸ , -SR ⁸ , -SO2NR ⁸ R ^{9 ,} -SO ^{2 OR 8} , -COOR ⁹ , ^{-COR 9 or -CONR 8 R 9 ,} each ^{of which} may be ^substituted or _{unsubstituted} ^{and R 8} , R ⁹ and R ¹⁰ are independently hydrogen, alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl, each of which may be substituted or unsubstituted; where R ⁸ and R ⁹ are located on a nitrogen atom, they may together form a 5- or 6-membered ring structure consisting of carbon atoms and one or more heteroatoms, which may be oxygen, sulfur or nitrogen atoms; or R ⁶ is hydrogen when R ¹³ is located at the 3-position of the phenyl ring and is not hydrogen; R is hydrogen, halogen, nitro, cyano, amino, halogenated alkyl, hydroxyl or the following groups, substituted or unsubstituted: straight or branched, C1-C12 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryl-oχι-, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO ₂ R ⁸ , -OCONR ⁸ R ⁹ , NR ⁸ a group of the general formula COOR ⁹ , -NR ⁸ COR ^S , NR ⁸ R ⁹ , -NR ⁸ SO2R ⁹ , -NR ⁸ CONR ⁹ R ¹⁰ , -NR ⁸ CSNR ⁸ R ⁹ , -SO2R ⁸ , -SOR ⁸ , -SR ⁸ , SO2NR ⁸ R ⁹ , -SO2OR ⁸ , -COOR ⁹ , -COR ⁹ , -CONR ⁸ R ⁹ , where R ⁸ , R ⁹ and R ¹⁰ independently represent a hydrogen atom or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; when R ⁸ and R ⁹ are on a nitrogen atom, they can together form a 5-6 membered ring structure consisting of carbon atoms and one or more heteroatoms, namely oxygen, sulfur or nitrogen atoms, intermediates, derivatives, analogs, tautomeric forms, stereoisomers, salts, solvates thereof. 8. A process for preparing a compound of general formula (IIIa) according to claim 7, its derivatives, analogues, tautomeric forms, stereoisomers, which comprises (a) (i) reacting a compound of general formula (IIIa) - where X is a group or bond of the formula -C(O)CH ₂ -, -CH=CH-CH ₂ -, R ⁶ and R ¹³ are as defined in claim 6 - with a compound of general formula (IIR) - where R ¹² is a hydrogen atom or a C 1-6 alkyl group, m is as defined above - to obtain a compound of general formula (IIIm) - where all symbols are as defined above -; (ii) and the compound of formula (IIIm) is converted in the presence of an acid or base to a compound of formula (IIIa), wherein ^R5 is hydrogen; X is a group or bond of the formula -C( _OCH2- , -CH=CH- _CH2- ); m is 0; Ar is phenyl, and all other symbols are as defined above; or 135 (b) reacting a compound of formula (IIIg) wherein all symbols are as defined above with a compound of formula (IIIn) wherein R ¹² is hydrogen or alkyl, m is an integer of 0-6, and R ⁵ is as defined above to obtain a compound of formula (IIIa) wherein R ⁵ is hydrogen or alkyl; m is 0 or 1, and all other symbols are as defined above. 9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-5, together with a pharmaceutically acceptable carrier, diluent, excipient or solvent. 10. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1-5 and an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, a hypoglycemic agent, an insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and PPAR-γ agonist or a mixture thereof, accompanied by a pharmaceutically acceptable carrier, diluent, excipient or solvent. 11. A pharmaceutical composition according to claim 9 or 10 in the form of a tablet, capsule, powder, syrup, solution or suspension. 12. A method for treating and/or preventing insulin resistance or impaired glucose tolerance, which comprises administering to a patient in need of treatment a compound of general formula (I) according to claims 1-5 or a pharmaceutical composition according to claims 9-10. 13. Method for treating diabetes or a complication of diabetes caused by insulin resistance or impaired glucose tolerance, wherein the complication of diabetes is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary heart disease, cardiovascular disease; kidney disease 136 gek, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy; retinopathy, diseases associated with endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, for the treatment and/or prevention of cancer or for use as an aldose reductase inhibitor or anti-inflammatory agent, which comprises administering a compound of general formula (I) according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 to a patient in need of treatment. 14. A method for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance, which comprises administering a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 to a patient in need of treatment. 15. A method for treating and/or preventing disorders associated with syndrome X, which comprises administering to a patient in need of treatment a compound of formula (I) according to any one of claims 15 or a pharmaceutical composition according to claim 9 or 10. 16. The method of claim 15, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease, or a cardiovascular disorder. 17. A method for reducing total cholesterol, body weight, blood plasma glucose, insulin, HbA _1c , triglyceride, LDL, VLDL and free fatty acid levels or increasing HDL levels, which comprises administering a compound of general formula (I) according to claims 1-5. A compound according to any one of claims 137 or a pharmaceutical composition according to claim 9 or 10 is administered to a patient in need of treatment. 18. A method for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance, which comprises administering to a patient in need of treatment an effective amount of a compound of general formula (I) according to claims 1-5 or a composition according to claim 9 or 10 in combination with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and PPAR-γ agonist or a mixture thereof, or in combination within a period of time during which their synergistic and/or additive effects are still exerted. 19. A method for treating diabetes or a complication of diabetes caused by insulin resistance or impaired glucose tolerance, wherein the complication of diabetes is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary heart disease, cardiovascular diseases; kidney diseases, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy; retinopathy, endothelial cell activation-related diseases, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer treatment and/or prevention or as an aldose reductase inhibitor or anti-inflammatory agent, which comprises administering to a patient in need of treatment an effective amount of a compound of formula (I) according to claims 1-5 or a composition according to claim 9 or 10. 138 ~··· ^: ..... ¹ CoA reductase inhibitor, cholesterol absorption inhibitor, anti-obesity agent, lipoprotein disorder treatment agent, hypoglycemic agent, insulin, biguanide, sulfonylurea, thiazolidinedione, dual PPAR-α and PPAR-γ agonist or a mixture thereof, or in combination within a period of time during which their synergistic and/or additive effects still prevail. 20. A method for treating and/or preventing disorders associated with syndrome X, comprising administering to a patient in need of treatment an effective amount of a compound of formula (I) according to claims 1-5 or a composition thereof according to claim 9 or 10, in combination with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for treating a lipoprotein disorder, a hypoglycemic agent, an insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and PPAR-γ agonist, or a mixture thereof, or in combination for a period of time during which their synergistic and/or additive effects are still present. 21. The method of claim 20, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease, or a cardiovascular disorder. 22. A method for reducing total cholesterol, body weight, blood plasma glucose, insulin, HbA1c, triglycerides, LDL, VLDL and free fatty acid levels or increasing HDL levels, which comprises administering to a patient in need of treatment an effective amount of a compound of formula (I) according to claims 1-5 or a composition thereof according to claim 9 or 10, in combination with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, a hypoglycemic agent, an insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and PPAR-γ agonist or a mixture thereof, or in combination for a period of time during which their synergistic and/or additive effects are still present. 23. Use of the compounds of general formula (I) according to any one of claims 1-5 or the composition according to claim 9 or 10 for the treatment and/or prevention of diabetes caused by insulin resistance or impaired glucose tolerance. 24. Use of a compound of formula (I) according to any one of claims 1 to 5 or a composition according to claim 9 or 10 for the treatment of diabetes or a complication of diabetes caused by insulin resistance or impaired glucose tolerance, wherein the complication of diabetes is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary heart disease, cardiovascular diseases; kidney diseases, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy; retinopathy, endothelial cell activation-related diseases, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, for the treatment and/or prevention of cancer or for use as an aldose reductase inhibitor or anti-inflammatory. 25. Use of a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance. 26. Use of a compound of formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prevention of disorders associated with syndrome X, which comprises the use of a PPAR-α and/or PPAR-γ agonist. ·· ·· ·· »«*J ·♦·· « · ·· · · 140 : 27. The use of claim 26, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease, or cardiovascular disorder. 28. Use of a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 for reducing total cholesterol, body weight, blood plasma glucose, insulin, HbA _1c , triglyceride, LDL, VLDL or free fatty acid levels or increasing HDL levels. 29. The combined use of a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 with an HMG CoA reductase inhibitor, an agent inhibiting cholesterol absorption, an anti-obesity agent, an agent for treating lipoprotein disorders, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and β agonist, or the use thereof within a period of time resulting in a synergistic and/or additive effect, for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, impaired glucose tolerance, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance. 30. Use of a compound of general formula (I) according to any one of claims 1-5 or a composition according to claim 9 or 10 for the treatment of diabetes or a complication of diabetes caused by insulin resistance or impaired glucose tolerance, wherein the complication of diabetes is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary heart disease, cardiovascular diseases; kidney diseases, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive .··. .··.*··: *·'· 141 .ίλ ; nephrosclerosis, nephropathy; retinopathy, endothelial cell activation-related diseases, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, nutritional disorders, for the treatment and/or prevention of cancer or for use as an aldose reductase inhibitor or anti-inflammatory agent. 31. The combined use of a compound of formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 with an HMG CoA reductase inhibitor, an agent inhibiting cholesterol absorption, an anti-obesity agent, an agent for treating a lipoprotein disorder, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and β agonist, or the use thereof within a period of time resulting in a synergistic and/or additive effect, for the treatment and/or prevention of disorders associated with Syndrome X, which comprises administering a PPAR-α and/or PPAR-γ agonist to a patient in need of treatment. 32. The use of claim 31, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease, or cardiovascular disorder. 33. The combined use of a compound of formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and γ agonist, or the use thereof within a period of time resulting in a synergistic and/or additive effect, for reducing total cholesterol, body weight, blood plasma glucose, insulin, HbAic, triglyceride, LDL, VLDL or free fatty acid levels or increasing HDL levels. 142 - . 34. A medicament for the treatment and/or prevention of diabetes caused by insulin resistance or impaired glucose tolerance, which comprises administering to a patient in need of treatment a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10. 35. A drug for the treatment of diabetes or complications of diabetes caused by insulin resistance or impaired glucose tolerance, where the complications of diabetes are dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary heart disease, cardiovascular diseases; kidney diseases, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy; retinopathy, endothelial cell activation-related diseases, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer for treatment and/or prevention or as an aldose reductase inhibitor or anti-inflammatory, which comprises administering a compound of general formula (I) according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 to a patient in need of treatment. 36. A medicament for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance, which comprises administering a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 to a patient in need of treatment. 143 • V ·· · * J.,·. · *- « 37. A medicament for the treatment and/or prevention of disorders associated with syndrome X, which comprises administering to a patient in need of treatment a PPAR-α and/or PPAR-γ agonist of general formula (I) according to claims 1-5 or a pharmaceutical composition according to claims 9 or 10. 38. The medicament of claim 37, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease, or a cardiovascular disorder. 39. A medicament for reducing total cholesterol, body weight, blood plasma glucose, insulin, HbA1c, triglyceride, LDL, VLDL and free fatty acid levels or increasing HDL levels, which comprises administering a compound of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 to a patient in need of treatment. 40. A medicament for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases whose pathophysiological mechanism is based on insulin resistance, which comprises administering to the patient in need of treatment an effective amount of the compound of general formula (I) according to claims 1-5 or the composition according to claim 9 or 10, in combination with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and γ agonist or a mixture thereof, or in combination within a period of time during which their synergistic and/or additive effects are still exerted. 41. A drug for the treatment of diabetes or a complication of diabetes caused by insulin resistance or impaired glucose tolerance, where the complication of diabetes is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, S . ·\ /-.°*? • w »·· -144* obesity, coronary heart disease, cardiovascular diseases; kidney diseases, non-bacterial inflammation of the kidneys (glomerulonephritis), glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy; retinopathy, diseases associated with endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, for the treatment and/or prevention of cancer or for use as an aldose reductase inhibitor or anti-inflammatory agent, which comprises administering a compound of general formula (I) according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 to a patient in need of treatment. 42. A medicament for the treatment and/or prevention of syndrome X-related disorders, which comprises administering to a patient in need of treatment a PPAR-α and/or PPAR-γ agonist of general formula (I) according to any one of claims 1-5 or a pharmaceutical composition according to claim 9 or 10 in combination with an HMG CoA reductase inhibitor, a cholesterol uptake inhibitor, an anti-obesity agent, an agent for the treatment of a lipoprotein disorder, a hypoglycemic agent, an insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and γ agonist or mixtures thereof, or using them together within a period of time when their synergistic and/or additive effect is still present. 43. The medicament of claim 42, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease, or cardiovascular disorder. 44. A medicament for reducing total cholesterol, body weight, blood plasma glucose, HbA-| _C , triglyceride, LDL, VLDL or free fatty acid levels or increasing HDL levels, which comprises administering to a patient in need of treatment a compound of general formula (I) according to claims 1-5 or a compound of claim 9 or 10. • ** · f fc* 145 <, an effective amount of the composition according to claim 8 is administered in combination with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, an agent for the treatment of lipoprotein disorders, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR-α and γ agonist or a mixture thereof, or within a period of time during which their synergistic and/or additive effects are still exerted. The authorized person: